US 20100204152A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0204152 A1 BeVec et al. (43) Pub. Date: Aug. 12, 2010

(54) USE OF GLUTEN EXORPHINC: ASA Publication Classification THERAPEUTICAGENT (51) Int. Cl. A638/08 (2006.01) A6IP35/00 (2006.01) (76) Inventors: Dorian Bevec, Germering (DE); A6IP 9/10 (2006.01) Fabio Cavalli, Beckenried (CH): A6IP3/04 (2006.01) Vera Cavalli, Muzzano (CH): A6IP37/06 (2006.01) Gerald Bacher, Germering (DE) A6IP 7/06 (2006.01) A6IP 7/02 (2006.01) A6IP37/08 (2006.01) A6IP27/02 (2006.01) Correspondence Address: A6IP II/06 (2006.01) WINSTEAD PC A6IP II/00 (2006.01) P.O. BOX SO784 A6IP 5/00 (2006.01) DALLAS, TX 75201 (US) A6IPL/I6 (2006.01) A6IP 9/02 (2006.01) A6IPI3/2 (2006.01) (21) Appl. No.: 12/677,468 (52) U.S. Cl...... 514/16 (57) ABSTRACT (22) PCT Filed: Sep. 9, 2008 The present invention is directed to the use of the peptide compound Ala-Val-Pro-Tyr-Pro-Gln-Arg-OH as a therapeu tic agent for the prophylaxis and/or treatment of cancer, autoimmune diseases, fibrotic diseases, inflammatory dis (86). PCT No.: PCT/EP08/07675 eases, neurodegenerative diseases, infectious diseases, lung diseases, heart and vascular diseases and metabolic diseases. S371 (c)(1), Moreover the present invention relates to pharmaceutical (2), (4) Date: Mar. 10, 2010 compositions preferably in form of a lyophilisate or liquide buffer solution or artificial mother milk formulation or mother milk substitute containing the peptide Ala-Val-Pro (30) Foreign Application Priority Data Tyr-Pro-Gln-Arg-OH optionally together with at least one pharmaceutically acceptable carrier, cryoprotectant, lyopro Sep. 11, 2007 (EP) ...... EPO7017747.2 tectant, excipient and/or diluent. US 2010/0204152 A1 Aug. 12, 2010

USE OF GLUTEN EXORPHIN CASA ing the inventive peptide or peptide combination. The peptide THERAPEUTICAGENT and peptide combination are especially useful for prophylaxis and/or treatment of cancer, Vasculitis and excessive angiogen esis in autoimmune disorders, systemic sclerosis (Sclero 0001. The present invention is directed to the use of the derma), multiple Sclerosis, Sjögren's disease, vascular mal peptide compound Ala-Val-Pro-Tyr-Pro-Gln-Arg as a thera formations in blood and lymph vessels, DiGeorge syndrome, peutic agent for the prophylaxis and/or treatment of cancer, hereditary haemorrhagic telangiectasia, cavernous heman autoimmune diseases, fibrotic diseases, inflammatory dis gioma, cutaneous hemangioma, lymphatic malformations, eases, neurodegenerative diseases, infectious diseases, lung transplant arteriopathy, atherosclerosis, vascular anasto diseases, heart and vascular diseases and metabolic diseases. moses, adipose tissue in obesity, chronic allograft rejections, skin diseases, psoriasis, warts, allergic dermatitis, Scar kel BACKGROUND OF THE INVENTION oids, pyogenic granulomas, blistering disease, Kaposi sar 0002 The identification of a therapeutic compound effec coma in AIDS patients, systemic Sclerosis, eye diseases, per tive for the prophylaxis and/or treatment of a disease can be sistent hyperplastic vitreous syndrome, diabetic retinopathy, based on the activity of the compound in a biological assay. A retinopathy of prematurity, choroidal neovascularization, biological assay that mimics a disease causative mechanism lung diseases, pulmonary hypertension, asthma, nasal polyps, can be used to test the therapeutic activity of a candidate rhinitis, chronic airway inflammation and obstruction peptide. (COPD), cystic fibrosis, acute lung injury, bronchiolitis oblit 0003. The causative mechanism of many diseases is the erans organizing pneumonia, gastrointestinal tract diseases, over activity of a biological pathway. A peptide that can inflammatory bowel disease, periodontal disease, ascites, reduce the activity of the biological pathway can be effective peritoneal adhesions, liver cirrhosis, reproductive system dis in the prophylaxis and/or treatment of the disease caused by eases, endometriosis, uterine bleeding, ovarian cysts, ovarian the over activity of the biological pathway. Similarly the hyperstimulation, bone and joint diseases, arthritis and syno causative mechanism of many diseases is the over production Vitis, osteomyelitis, osteophyte formation, HIV-induced bone of a biological molecule. A peptide that can reduce the pro marrow angiogenesis, kidney diseases, early diabetic nephr duction of the biological molecule or block the activity of the opathy and other diseases which are described in the follow over produced biological molecule can be effective in the 1ng prophylaxis and/or treatment of the disease caused by the 0008 Cancer, tumors, proliferative diseases, malignan over production of the biological molecule. cies and their metastases The term "cancer as used herein 0004 Conversely, the causative mechanism of many dis refers also to tumors, proliferative diseases, malignancies and eases is the under activity of a biological pathway. A peptide their metastases. Examples for cancer diseases are adenocar that can increase the activity of the biological pathway can be cinoma, choroidal melanoma, acute leukemia, acoustic neu effective in the prophylaxis and/or treatment of the disease rinoma, ampullary carcinoma, anal carcinoma, astrocytoma, caused by the under activity of the biological pathway. Also basal cell carcinoma, pancreatic cancer, desmoid tumor, blad similarly the causative mechanism of many is the under pro der cancer, bronchial carcinoma, non-Small cell lung cancer duction of a biological molecule. A peptide that can increase (NSCLC), breast cancer, Burkitt's lymphoma, corpus cancer, the production of the biological molecule or mimic the bio CUP-syndrome (carcinoma of unknown primary), colorectal logical activity of the underproduced biological molecule can cancer, Small intestine cancer, Small intestinal tumors, ova be effective in the prophylaxis and/or treatment of the disease rian cancer, endometrial carcinoma, ependymoma, epithelial caused by the under production of the biological molecule. cancertypes, Ewing's tumors, gastrointestinal tumors, gastric 0005. It is the object of the present invention to provide a cancer, gallbladder cancer, gallbladder carcinomas, uterine compound for the prophylaxis and/or treatment of cancer, cancer, cervical cancer, cervix, glioblastomas, gynecologic autoimmune diseases, fibrotic diseases, inflammatory dis tumors, ear, nose and throat tumors, hematologic neoplasias, eases, neurodegenerative diseases, infectious diseases, lung hairy cell leukemia, urethral cancer, skin cancer, skin testis diseases, heart and vascular diseases and metabolic diseases. cancer, brain tumors (gliomas), brain metastases, testicle can 0006. The object of the present invention is solved by the cer, hypophysis tumor, carcinoids, Kaposi's sarcoma, laryn teaching of the independent claims. Further advantageous geal cancer, germ cell tumor, bone cancer, colorectal carci features, aspects and details of the invention are evident from noma, head and neck tumors (tumors of the ear, nose and the dependent claims, the description, and the examples of the throat area), colon carcinoma, craniopharyngiomas, oral can present application. cer (cancer in the mouth area and on lips), cancer of the central nervous system, liver cancer, liver metastases, leuke DESCRIPTION OF THE INVENTION mia, eyelid tumor, lung cancer, lymph node cancer (Hodgkin’s/Non-Hodgkin’s), lymphomas, stomach cancer, 0007. The present invention relates to the use of the pep malignant melanoma, malignant neoplasia, malignant tumors tide Ala-Val-Pro-Tyr-Pro-Gln-Arg as a therapeutic com gastrointestinal tract, breast carcinoma, rectal cancer, pound in medicine and for prophylaxis and/or treatment of medulloblastomas, melanoma, meningiomas, Hodgkin's dis cancer, autoimmune diseases, fibrotic diseases, inflammatory ease, mycosis fungoides, nasal cancer, neurinoma, neuroblas diseases, neurodegenerative diseases, infectious diseases, toma, kidney cancer, renal cell carcinomas, non-Hodgkin’s lung diseases, heart and vascular diseases and metabolic dis lymphomas, oligodendroglioma, esophageal carcinoma, eases. Furthermore, the present invention relates to the com osteolytic carcinomas and osteoplastic carcinomas, osteosa bination and use of the combination of the peptides Tyr-Pro rcomas, ovarial carcinoma, pancreatic carcinoma, penile can Ile-Ser-Leu-OH. Also disclosed are pharmaceutical cer, plasmocytoma, squamous cell carcinoma of the head and formulations preferably in form of a lyophilisate or liquid neck (SCCHN), prostate cancer, pharyngeal cancer, rectal buffer solution or artificial mother milk formulation contain carcinoma, retinoblastoma, vaginal cancer, thyroid carci US 2010/0204152 A1 Aug. 12, 2010 noma, Schneeberger disease, esophageal cancer, spinalioms, (American trypanosomiasis), chickenpox (Varicella-Zoster T-cell lymphoma (mycosis fungoides), thymoma, tube carci virus), Chlamydia pneumoniae infection, cholera, noma, eye tumors, urethral cancer, urologic tumors, urothe Creutzfeldt-Jakob disease (CJD), clonorchiasis (Clonorchis lial carcinoma, Vulva cancer, wart appearance, Soft tissue infection), cutaneous larva migrans (CLM) (hookworm tumors, soft tissue sarcoma, Wilm's tumor, cervical carci infection), coccidioidomycosis, conjunctivitis, Coxsackievi noma and tongue cancer. rus A16 (hand, foot and mouth disease), cryptococcosis, 0009. The peptides and peptide combination of the present Cryptosporidium infection (cryptosporidiosis), Culex mos invention was tested using the assays described in Examples quito (West Nile virus vector), cyclosporiasis (Cyclospora 1-7, 9-17 for their effect as active therapeutic agents in the infection), cysticercosis (neurocysticercosis), Cytomegalovi prophylaxis and/or treatment of cancer, proliferative dis rus infection, Dengue/Dengue fever, Dipylidium infection eases, tumors and their metastases. (dog and cat flea tapeworm), Ebola virus hemorrhagic fever, 0010 Infectious Disease encephalitis, Entamoeba coli infection, Entamoeba dispar 0011. The immune system in higher vertebrates represents infection, Entamoeba hartmanni infection, Entamoeba his the first line of defense against various antigens that can enter tolytica infection (amebiasis), Entamoeba polecki infection, the vertebrate body, including microorganisms such as bac enterobiasis (pinworm infection), enterovirus infection (non teria, fungi and viruses that are the causative agents of a polio), Epstein-Barr virus infection, Escherichia coli infec variety of diseases. tion, foodborne infection, foot and mouth disease, fungal 0012 Despite large immunization programs, viral infec dermatitis, gastroenteritis, group A Streptococcal disease, tions, such as influenza virus, human immunodeficiency virus group B streptococcal disease, Hansen's disease (leprosy), (“HIV), herpes simplex virus (“HSV”, type 1 or 2), human Hantavirus pulmonary syndrome, head lice infestation (pe papilloma virus (“HPV, type 16 or 18), human cytomega diculosis), Helicobacter pylori infection, hematologic dis lovirus (“HCMV) or human hepatitis B or C virus (“HBV, ease, Hendra virus infection, hepatitis (HCV. HBV), herpes Type B; "HCV, type C) infections, remain a serious source Zoster (shingles), HIV Infection, human ehrlichiosis, human of morbidity and mortality throughout the world and a sig parainfluenza virus infection, influenza, isosporiasis (Isos nificant cause of illness and death among people with pora infection), Lassa fever, leishmaniasis, Kala-azar (Kala immune-deficiency associated with aging or different clinical azar, Leishmania Infection), lice (body lice, head lice, pubic conditions. Although antiviral chemotherapy with com lice), Lyme disease, malaria, Marburg hemorrhagic fever, pounds such as amantadine and rimantadine have been shown measles, meningitis, mosquito-borne diseases, Mycobacte to reduce the duration of symptoms of clinical infections (i.e., rium avium complex (MAC) infection, Naegleria infection, influenza infection), major side effects and the emergence of nosocomial infections, nonpathogenic intestinal ameobae drug-resistant variants have been described. New classes of infection, onchocerciasis (river blindness), opisthorciasis antiviral agents designed to target particular viral proteins (Opisthorcis infection), parvovirus infection, plague, Pneu Such as influenza neuraminidase are being developed. How mocystis carinii pneumonia (PCP), polio, Q fever, rabies, ever, the ability of viruses to mutate the target proteins rep respiratory syncytial virus (RSV) Infection, rheumatic fever, resents an obstacle for effective treatment with molecules Rift Valley fever, river blindness (onchocerciasis), rotavirus which selectively inhibit the function of specific viral infection, roundworm infection, salmonellosis, salmonella polypeptides. Thus, there is need for new therapeutic strate enteritidis, Scabies, Shigellosis, shingles, sleeping sickness, gies to prevent and treat viral infections. Smallpox, Streptococcal Infection, tapeworm infection (Tae 0013 Additionally, there is a need for new therapies for nia infection), tetanus, toxic shock syndrome, tuberculosis, the prevention and treatment of bacterial infections, espe ulcers (peptic ulcer disease), Valley fever, Vibrio para cially bacterial infections caused by multiple drug resistant haemolyticus infection, Vibrio vulnificus infection, viral hem bacteria. Currently, bacterial infections are treated with vari orrhagic fever, warts, waterborne infectious diseases, West ous antibiotics. Although antibiotics have and can be effective Nile virus infection (West Nile encephalitis), whooping in the treatment of various bacterial infections, there are a cough, yellow fever. number of limitations to the effectiveness and safety of anti 0016. Another aspect of the present invention is directed to biotics. For example, some individuals have an allergic reac the use of the peptide or the peptide combination for prophy tion to certain antibiotics and other individuals suffer from laxis and/or treatment of prion diseases. serious side effects. Moreover, continued use of antibiotics 0017 Prions are infectious agents which do not have a for the treatment of bacterial infections contributes to forma nucleic acid genome. It seems that a protein alone is the tion of antibiotic-resistant strains of bacteria. infectious agent. A prion has been defined as 'small proteina 0014) Another aspect of the present invention is directed to ceous infectious particle which resists inactivation by proce the use of the peptide or the peptide combination for prophy dures that modify nucleic acids”. The discovery that proteins laxis and/or treatment of infectious diseases including oppor alone can transmit an infectious disease came as a consider tunistic infections. able Surprise to the Scientific community. Prion diseases are 00.15 Examples of infectious diseases are AIDS, alveolar often called “transmissible spongiform encephalopathies”. hydatid disease (AHD, echinococcosis), amebiasis (Entam because of the post mortem appearance of the brain with large oeba histolytica infection), Angiostrongylus infection, vacuoles in the cortex and cerebellum. Probably most mam anisakiasis, anthrax, babesiosis (Babesia infection), Balan malian species develop these diseases. Prion diseases are a tidium infection (balantidiasis), Baylisascaris infection (rac group of neurodegenerative disorders of humans and animals coon roundworm), bilharzia (Schistosomiasis), Blastocystis and the prion diseases can manifest as sporadic, genetic or hominis infection (blastomycosis), boreliosis, botulism, infectious disorders. Examples of prion diseases acquired by Brainerd diarrhea, brucellosis, bovine spongiform encephal exogenous infection are bovine spongiform encephalitis opathy (BSE), candidiasis, capillariasis (Capillaria infec (BSE) of cattle and the new variant of Creutzfeld-Jakob dis tion), chronic fatigue syndrome (CFS), Chagas disease ease (VCJD) caused by BSE as well as scrapie of animals. US 2010/0204152 A1 Aug. 12, 2010

Examples of human prion diseases include kuru, sporadic arthritis has long been considered to involve phagocytosis by Creutzfeldt-Jakob disease (sCJD), familial CJD (f(JD), leukocytes of complexes of antigen, antibody and comple iatrogenic CJD (iCJD), Gerstmann-Sträussler-Scheinker ment-immune complexes. However, only now it is being rec (GSS) disease, fatal familial insomnia (FFI), and especially ognized that inflammation caused by immune complexes in the new variant CJD (nvCJD or vCJD). the joints (arthritis), the kidneys (glomerulonephritis), and 0018. The name “prion' is used to describe the causative blood vessels (vasculitis) is a major cause of morbidity in agents which underlie the transmissible spongiform encepha autoimmune diseases. Increased immune complex formation lopathies. A prion is proposed to be a novel infectious particle correlates with the presence of antibodies directed to self or that differs from viruses and viroids. It is composed solely of so-called autoantibodies, and the presence of the latter can one unique protein that resists most inactivation procedures also contribute to tissue inflammation either as part of an Such as heat, radiation, and proteases. The latter characteristic immune complex or unbound to antigen (free antibody). In has led to the term protease-resistant isoform of the prion Some autoimmune diseases, the presence of free autoanti protein. The protease-resistant isoform has been proposed to body contributes significantly to disease pathology. This has slowly catalyze the conversion of the normal prion protein been clearly demonstrated for example in SLE (anti-DNA into the abnormal form. antibodies), immune thrombocytopenia (antibody response 0019. The term “isoform' in the context of prions means directed to platelets), and to a lesser extent rheumatoid arthri two proteins with exactly the same amino acid sequence that tis (IgG reactive rheumatoid factor). The important role of can fold into molecules with dramatically different tertiary immune complexes and free autoantibodies is further dem structures. The normal cellular isoform of the prion protein onstrated by the fact that successful treatment of certain (PrP) has a high C-helix content, a low B-sheet content, and autoimmune diseases has been achieved by the removal of is sensitive to protease digestion. The abnormal, disease immune complexes and free antibody by means of specific causing isoform (PrP) has a lower C-helix content, a much immunoadsorption procedures. For example, the use of an higher B-sheet content, and is much more resistant to protease apheresis procedure in which immune complexes and anti digestion. bodies are removed by passage of a patient’s blood through an 0020. As used herein the term “prion diseases’ refers to immunoaffinity column was approved by the U.S. FDA in transmissible spongiform encephalopathies. Examples for 1987 for immune thrombocytopenia (ITP) and in 1999 for prion diseases comprise scrapie (sheep, goat), transmissible rheumatoid arthritis. However, currently there is no approved mink encephalopathy (TME, mink), chronic wasting disease method for the treatment of autoimmune diseases which (CWD; muledeer, deer, elk), bovine spongiform encephal facilitates the elimination of immune complexes and autoan opathy (BSE: cows, cattles), Creutzfeld-Jacob Disease tibodies by administration of a drug. (CJD), variant CJD (VCJD), sporadic Creutzfeldt-Jakob dis 0026. Another aspect of the etiology and progression of ease (SCJD), familial CJD (f(JD), iatrogenic CJD (iCJD. autoimmune disease is the role of proinflammatory cytokines. Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal Under normal circumstances, proinflammatory cytokines familial insomnia (FFI), and kuru. Preferred are BSE, VCJD. such as tumor necrosis factor C. (TNFC.) and interleukin-1 and CJD. (1L-1) play a protective role in the response to infection and 0021. The peptides of the present invention were tested cellular stress. However, the pathological consequences using the assays described in Examples 1-7 for their effect as which result from chronic and/or excessive production of active therapeutic agents in the prophylaxis and/or treatment TNFC. and IL-1 are believed to underlie the progression of of infectious diseases and disorders. many autoimmune diseases such as rheumatoid arthritis, 0022 Autoimmune Disease Crohn's disease, inflammatory bowel disease, and psoriasis. 0023 Autoimmune disease refers to any of a group of Other proinflammatory cytokines include interleukin-6, diseases or disorders in which tissue injury is associated with interleukin-8, interleukin-17, and granulocyte-macrophage a humoral and/or cell-mediated immune response to body colony stimulating factor. constituents or, in a broader sense, an immune response to 0027 Naturally occurring CD4+CD25+ regulatory T cells self. The pathological immune response may be systemic or (Tregs) play a critical role in the control of periphery toler organ specific. That is, for example, the immune response ance to self-antigens. Interestingly, they also control immune directed to self may affect joints, skin, myelin sheath that responses to allergens and transplantantigens. Recent studies protects neurons, kidney, liver, pancreas, thyroid, adrenals, in animal models have shown that adoptive transfer of CD4+ and ovaries. CD25+ Tregs can prevent or even cure allergic and autoim 0024. In fact, the list of autoimmune diseases is composed mune diseases, and appear to induce transplantation toler of more than eighty disorders. A few autoimmune diseases ance. Thus, adoptive cell therapy using patient-specific CD4+ Such as vitiligo, in which patches of skin lose pigmentation, CD25+ Tregs has emerged as an individualized medicine for are merely annoying. Most others are debilitating, often pro the treatment of inflammatory disease including allergy, gressive with time and eventually fatal. Systemic lupus autoimmune disease and transplant rejection. Furthermore, erythematosus (SLE), for example, is a chronic disease in strategies to activate and expand antigen-specific CD4+ which 10-15% of patients die within a decade of diagnosis, in CD25+Tregs in vivo using pharmacological agents may rep all but a few autoimmune diseases, the sex ratio skews resent a novel avenue for drug development. towards women. For example, in SLE the ratio of female to 0028. The interaction of leukocytes with the vessel endot male patients is nine to one. In one particular case, Hashimo helium to facilitate the extravasation into the tissue represents to's disease in which the immune system attacks the thyroid a key process of the body's defense mechanisms. Excessive gland, the ratio is fifty to one. recruitment of leukocytes into the inflamed tissue in chronic 0025. It has long been known that immune complex for diseases like autoimmune disorders could be prevented by mation plays a role in the etiology and progression of autoim interfering with the mechanisms of leukocyte extravasation. mune disease. For example, inflammation in patients with Significant progress in elucidating the molecular basis of the US 2010/0204152 A1 Aug. 12, 2010 trafficking of leukocytes from the blood stream to the drome, multiple Sclerosis, multifocal motoric neuropathy, extravascular tissue has been achieved that enables new strat myasthenia gravis, paraneoplastic neurological syndrome, egies for therapeutic approaches. The multistep process of Rasmussen's encephalitis, and stiff-man syndrome. leukocyte rolling, firm adhesion and transmigration through 0041. Examples of autoimmune diseases of the kidney are the endothelial wall is facilitated by a dynamic interplay of anti-TBM-nephritis, Goodpasture's syndrome/anti-GBM adhesion receptors on both leukocytes and on endothelial nephritis, IgA-nephropathy, interstitial nephritis, and mem cells as well as chemokines. In preclinical studies using vari brane proliferative glomerulonephritides. ous animal models, promising results have been obtained 0042. Further diseases that may be caused by an autoim demonstrating that blocking of adhesion receptors of the mune reaction are Behcet disease, chronic fatigue immune selectin and integrin families improved the inflammation pro dysfunction syndrome (CFIDS), Cogan syndrome I, cess in models of ulcerative colitis, autoimmune encephalo endometriosis, HELLP syndrome. Bechterew's disease, myelitis or contact hyperSensitivity. In addition to the target polymyalgia rheumatica, psoriasis, sarcoidosis and vitiligo. ing of adhesion receptors by antibodies, Small molecules that 0043. During the last decade, new biotherapies have been mimic epitopes of adhesion receptor ligands have been devel developed for the treatment of systemic autoimmune dis oped and Successfully applied in animal models. Clinical eases. The targets of these new treatments are all the steps of studies revealed a limited response using antibodies to selec the immune response. These new therapies are: B lymphocyte tins or leukocyte function-associated antigen 1 (LFA-1) inte (BL) inhibitors such as anti-CD20 monoclonal antibody, B grins compared with animal models. However, using human lymphocyte stimulator (BLyS) antagonists and tolerogens of ized antibodies to the alpha 4-integrin Subunit significant pathogenic-antibody secreting LB: inhibitors of the costimu efficacy has been demonstrated in autoimmune diseases like lation between antigen-presenting cells and T lymphocyte psoriasis, multiple Sclerosis and inflammatory bowel disease. (TL) like monoclonal anti-CD40 ligandantibody or CTLA4 0029. Examples of autoimmune diseases of the eyes are Ig (abatecept); TL antagonists which can inhibit the prolif idiopathic opticus-neuritis, ophthalmia sympathica, anterior eration of autoreactive T cells; cytokine antagonists; chemok uveitis and other uveitis forms, retina degeneration, and ine and adhesin antagonists which inhibit trafficking of Mooren's ulcer. immunocompetent cells to target organs. These new 0030 Examples of autoimmune diseases of the skin are approaches are based on a better understanding of the autoim bullous pemphigoides, chronic urticaria (autoimmune Sub mune response. type), dermatitis herpetiformis (morbus Duhring), epider 0044) The peptide or the peptide combination of the molysis bullosa aquisita (EBA), acquired angioedema, her present invention were tested using the assays described in pes gestationes, hypocomplementemic urticarial vasculitis Examples 14-15 for their effect as active therapeutic agents in syndrome (HUVS), linear IgA-dermatosis, and pemphigus. the prophylaxis and/or treatment of autoimmune diseases and 0031 Examples of hematological autoimmune diseases disorders. are autoimmune hemolytic anemia, autoimmune neutrope 0045 Fibrotic Disease nia, Evans syndrome, inhibitor hemophilia, idiopathic throm 0046 Fibrosis or fibrosis associated disorder affects the bocytopenial purpura (ITP) and pernicious anemia. liver, epidermis, endodermis, muscle, tendon, cartilage, 0032 Examples of gynecological autoimmune diseases heart, pancreas, lung, uterus, nervous system, testis, ovary, are habitual abortion and infertility. adrenal gland, artery, vein, colon, Small intestine, biliary tract, 0033 Examples of autoimmune diseases of the heart are or stomach. In a further embodiment, the fibrosis or fibrosis congenital heart block, idiopathic dilatative cardiomyopathy, associated disorder is interstitial lung fibrosis. In another peripartum-cardiomyopathy, postcardiotomy syndrome, and embodiment the fibrosis or fibrosis associated disorder is the postinfarct syndrome (Dressler syndrome). result of an infection with schistosoma. In another embodi 0034 Examples of autoimmune diseases of the ear, nose ment the fibrosis or fibrosis associated disorder is the result of and throat are chronic sensorineural hearing loss and morbus wound healing. Meniére. 0047 Fibrosis is generally characterized by the pathologic 0035 Examples of autoimmune diseases of the colon are or excessive accumulation of collagenous connective tissue. autoimmune enteropathy, colitis ulcerosa, indeterminant Fibrotic diseases and disorders include, but are not limited to, colitis, Crohn's disease and gluten-sensitive enteropathy. collagen disease, interstitial lung disease, human fibrotic lung 0036) Examples of autoimmune endocrinological autoim disease (e.g., obliterative bronchiolitis, idiopathic pulmonary mune disorders are autoimmune polyglandulary syndrome fibrosis, pulmonary fibrosis from a known etiology, tumor type 1, autoimmune polyglandulary syndrome type 2, diabe stroma in lung disease, systemic Sclerosis affecting the lungs, tes mellitus type 1 (IDDM), Hashimoto-thyroiditis, insulin Hermansky-Pudlak syndrome, coal worker's pneumoconio autoimmune-syndrome (IAS), idiopathic diabetes insipidus, sis, asbestosis, silicosis, chronic pulmonary hypertension, idiopathic hypoparathyroidism, idiopathic Addison's disease AIDS associated pulmonary hypertension, sarcoidosis, and and Graves-Basedow disease. the like), fibrotic vascular disease, tubulointerstitial and 0037 Examples of autoimmune diseases of the liver are glomerular fibrosis, myocardial fibrosis, arterial sclerosis, autoimmune hepatitis (AIH type 1, 2 and 3), primary biliary atherosclerosis, varicose veins, coronary infarcts, cerebral cirrhosis (PBC), and primary Sclerosing cholangitis. infarcts, myocardial fibrosis, musculoskeletal fibrosis, post 0038 Example of autoimmune diseases of the lung is Surgical adhesions, human kidney disease (e.g., nephritic Goodpasture's syndrome. syndrome, Alport's syndrome, HIV associated nephropathy, 0039. An example of an autoimmune disease of the stom polycystic kidney disease, Fabry's disease, diabetic nephr ach is chronic atrophic (type A) gastritis. opathy, chronic glomerulonephritis, nephritis associated with 0040. Examples of neurological autoimmune disorders systemic lupus, and the like), cutiskeloid formation, progres are Guillain-Barré syndrome, IgM gammopathy-associated sive systemic Sclerosis (PSS), primary Sclerosing cholangitis neuropathy, Lambert-Eaton syndrome, Miller-Fisher syn (PSC), liver fibrosis, liver cirrhosis, renal fibrosis, pulmonary US 2010/0204152 A1 Aug. 12, 2010

fibrosis, cystic fibrosis, chronic graft versus host disease, fibroblast may be the key to understanding why certain forms Scleroderma (local and systemic), Grave's opthalmopathy, of lung injury may result in progressive disease, terminating diabetic retinopathy, glaucoma, Peyronio's disease, penis in end stage disease. fibrosis, urethrosteriosis after a test using a cystoscope, inner 0.052 Although pulmonary fibrosis has diverse etiologies, accretion after Surgery, Scarring, myelofibrosis, idiopathic there is a common feature characteristic of this process, retroperitoneal fibrosis, peritoneal fibrosis from a known eti namely, the abnormal deposition of extracellular matrix that ology, drug induced ergotism, fibrosis incident to benign or effaces the normal lung tissue architecture. A key cellular malignant cancer, fibrosis incident to microbial infection Source of this matrix is the mesenchymal cell population that (e.g., viral, bacterial, parasitic, fungal, etc.), Alzheimer's dis occupies much of the fibrotic lesion during the active period offibrosis. This population is heterogeneous with respect to a ease, fibrosis incident to inflammatory bowel disease (includ number of key phenotypes. One of these phenotypes is the ing stricture formation in Crohn's disease and microscopic myofibroblast, which is commonly identified by its expres colitis), fibrosis induced by chemical or environmental insult sion in C-Smooth muscle actin and by features that are inter (e.g., cancer chemotherapy, pesticides, radiation/cancer mediate between the bona fide smooth muscle cell and the radiotherapy), and the like. fibroblast. The de novo appearance of myofibroblasts at sites 0048 Diseases associated with fibrosis include lupus, of wound healing and tissue repair/fibrosis is associated with graft versus host disease, Scleroderma, systemic sclerosis, the period of active fibrosis and is considered to be involved in Scleroderma-like disorders, sine Scleroderma, calcinosis, wound contraction. Furthermore, the localization of myofi Raynaud's esophageal dysfunction, Sclerodactyly, telang broblasts at sites undergoing active extracellular matrix depo iectasiae, hypersensitivity pneumonitis, collagen vascular sition Suggests an important role for these cells in the genesis disease, asthma, pulmonary arterial hypertension, glomeru of the fibrotic lesion. lonephritis, chronic obstructive pulmonary disease, fibrosis 0053 Increased TGF-/B Family Levels in Fibrotic Dis following myocardial infarction, central nervous system CaSS fibrosis following a stroke or neuro-degenerative diseases 0054) The transforming growth factor-B (TGF-B) family (e.g. Alzheimer's disease), proliferative vitreoretinopathy of proteins has the most potent stimulatory effect on extra (PVR) and arthritis, silicosis, asbestos induced pulmonary cellular matrix deposition of any cytokines so far examined. fibrosis, acute lung injury and acute respiratory distress Syn In animal models of pulmonary fibrosis enhanced TGF-B drome (including bacterial pneumonia induced, trauma gene expression is temporally and spatially related to induced, viral pneumonia induced, tuberculosis, ventilator increased collagen gene expression and protein deposition. induced, non-pulmonary sepsis induced, and aspiration TGF-B antibodies reduce collagen deposition in murine bleomycin-induced lung fibrosis and human fibrotic lung tis induced). Sue shows enhanced TGF-B gene and protein expression. 0049. Increased Number of Activated Myofibroblasts in Several lines of evidence suggest that TGF-B is a central Fibrotic Diseases regulator of pulmonary fibrosis. Several animal models over 0050. The emergence and disappearance of the myofibro expressing TGF-B showed extensive progressive fibrosis but blast appears to correlate with the initiation of active fibrosis limited inflammation, indicating that TGF-B may play a pre and its resolution, respectively. In addition, the myofibroblast dominant role in the progression of pulmonary fibrosis. has many phenotypic features, which embody much of the Therapeutic efforts are therefore focusing on inhibition of pathologic alterations in fibrotic tissue, e.g. lung tissue. These TGF-B activity, for instance by anti-TGF-31-antibodies, or features would seem to argue for an important role for the modulators of TGF-31 such as pirfenidone. Pirfenidone myofibroblast in the pathogenesis of fibrosis, e.g. lung fibro inhibits TGF-B1 gene expression in vivo resulting in inhibi sis. Furthermore, the persistence of the myofibroblast may tion of TGF-31-mediated collagen synthesis and appears to herald progressive disease, and, conversely, its disappearance slow progression of IPF in patients. Other novel, promising may be an indicator of resolution. This in turn suggests that antifibrotic agents include relaxin (inhibits TGF-3-mediated future therapeutic strategies targeting the myofibroblast overexpression of collagen and increases collagenases), would be productive. Suramin (inhibits growth factors), prostaglandin E2 (inhibits 0051 Patients usually exhibit evidence of active fibrosis collagen production) and lovastatin (blocks formation of with increased numbers of activated fibroblasts, many of granulation tissue by induction of fibroblast apoptosis). which have the phenotypic characteristics of myofibroblasts. 0055 Diseases involving the lung associated with At these sites, increased amounts of extracellular matrix increased levels of TGF-B include chronic lung disease of deposition are evident with effacement of the normal alveolar prematurity, idiopathic pulmonary fibrosis, rapid progressive architecture. Animal model studies show the myofibroblast to pulmonary fibrosis, giant-cell interstitial pneumonia, acute be the primary Source of type I collagen gene expression in rejection after lung transplantation, cytomegalovirus pneu active fibrotic sites. In vitro studies show differentiation of monitis after lung transplantation, bronchiolitis obliterans, these cells from fibroblasts under the influence of certain asbestosis, coal worker's pneumoconiosis, silicosis, histiocy cytokines but indicate their susceptibility to nitric oxide tosis, sarcoidosis, eosinophilic granuloma, Scleroderma, sys mediated apoptosis. In addition to promoting myofibroblast temic lupus erythematosus, lymphangioleiomyomatosis, differentiation, transforming growth factor-f1 (TGF-31) pro central fibrosis inpulmonary adenocarcinoma, cystic fibrosis, vides protection against apoptosis. Thus, this well-known chronic obstructive lung disease, and asthma. fibrogenic cytokine is important both for the emergence of the 0056 Increased TNF-C. Levels in Fibrotic Diseases myofibroblast and its survival againstapoptotic stimuli. This 0057. An important role of tumor necrosis factor-O. (TNF is consistent with the critical importance of this cytokine in C.) in interstitial fibrosis has been established using transgenic diverse models of fibrosis in various tissues. In view of these mice, which either overexpress or display a deficiency of this properties, the persistence or prolonged Survival of the myo cytokine. Mice transgenically modified to overexpress US 2010/0204152 A1 Aug. 12, 2010

TNF-C. develop lung fibrosis. In contrast, mice null for the pathogenesis of pulmonary fibrosis Such as insulin-like TNF-C. show marked resistance to bleomycin induced fibro growth factor (IGF). TGF-B and TNF-C. occur through the sis. TNF-C. can stimulate fibroblast replication and collagen actions of MMPs, thereby activating or releasing them from synthesis in vitro, and pulmonary TNF-C. gene expression inhibitory protein-protein interactions. For example, IGFs in rises after administration of bleomycin in mice. Soluble vivo are sequestered by six high affinity IGF binding proteins TNF-C. receptors reduce lung fibrosis in murine models and (IGFBPs 1-6), preventing their ability to interact with IGF pulmonary overexpression of TNF-C. in transgenic mice is receptors. Studies examining adults and children IPF and characterized by lung fibrosis. In patients with CFA or asbes interstitial lung disease show that beside IPF, IGFBP-3 and tosis, bronchoalveolar lavage fluid-derived macrophages IFPB-2 levels are increased in IPF BAL fluid. MMPs have release increased amounts of TNF-C. compared with controls. recently been shown to regulate the cleavage of IGF binding 0058 Increased TNF-C. may induce fibrosis or fibrosis proteins, thereby liberating the complexed ligand to affect associated conditions affecting any tissue including, for IGF actions in target cells. Observations have also shown that example, fibrosis of an internal organ, a cutaneous or dermal the gelatinases, MMP-9 and MMP-2 may be involved in fibrosing disorder, and fibrotic conditions of the eye. Fibrosis proteolytic activation of latent TGF-B complexes. Further of internal organs (e.g., liver, lung, kidney, heart blood ves more, the MMP inhibitor Batimastat reduces MMP-9 activity sels, gastrointestinal tract) occurs in disorders such as pulmo in BAL fluid, which was associated with decreased amount of nary fibrosis, idiopathic fibrosis, autoimmune fibrosis, TGF-B and TNF-C. myelofibrosis, liver cirrhosis, veno-occlusive disease, mesan 0061 Pulmonary fibrosis can be an all too common con gial proliferative glomerulonephritis, crescentic glomerulo sequence of an acute inflammatory response of the lung to a nephritis, diabetic nephropathy, renal interstitial fibrosis, host of inciting events. Chronic lung injury due to fibrotic renal fibrosis in Subjects receiving cyclosporin, allograft changes can result from an identifiable inflammatory event or rejection, HTV associated nephropathy. Other fibrosis-asso an insidious, unknown event. The inflammatory process can ciated disorders include systemic sclerosis, eosinophilia-my include infiltration of various inflammatory cell types, such as algia syndrome, and fibrosis-associated CNS disorders such neutrophils and macrophages, the secretion of inflammatory as intraocular fibrosis. Dermal fibrosing disorders include, for cytokines and chemokines and the Secretion of matrix remod example, Scleroderma, morphea, keloids, hypertrophic scars, eling proteinases. familial cutaneous collagenoma, and connective tissue nevi 0062 Increased CCL18 Levels in Fibrotic Diseases of the collagen type. Fibrotic conditions of the eye include 0063. The expression and regulation of cysteine-cysteine conditions such as diabetic retinopathy, post-surgical scarring (CC) chemokine ligand 18 (CCL18), a marker of alternative (for example, after glaucoma filtering Surgery and after activation, by human alveolar macrophages (AMs) is crossed-eyes (strabismus) Surgery), and proliferative vitreo increased in patients with pulmonary fibrosis and correlates retinopathy. Additional fibrotic conditions that may be treated negatively with pulmonary function test parameters. Thus, by the methods of the present invention may result, for CCL18 is an ideal diagnostic marker for pulmonary fibrosis. example, from rheumatoid arthritis, diseases associated with 0064. The peptide or the peptide combination of the prolonged joint pain and deteriorated joints; progressive sys present invention were tested using the assays described in temic sclerosis, polymyositis, dermatomyositis, eosinophilic Examples 14-15 for their effect as active therapeutic agents in fasciitis, morphea, Raynaud's syndrome, and nasal polyposis. the prophylaxis and/or treatment of fibrotic diseases and dis 0059. Increased Matrix Metalloproteases Levels in orders. Fibrotic Diseases 0065 Inflammatory Disease 0060. The abnormal extracellular matrix (ECM) remodel 0.066 Inflammation is the final common pathway of vari ing observed in the lungs of patients with interstitial pulmo ous insults, such as infection, trauma, and allergies to the nary fibrosis (IPF) is due, at least in part, to an imbalance human body. It is characterized by activation of the immune between matrix metalloproteases (MMPs) and tissue inhibi system with recruitment of inflammatory cells, production of tor of metalloproteinases (TIMPs). Normal lung fibroblasts pro-inflammatory cells and production of pro-inflammatory do not make MMP-9 in vitro, whereas fibroblasts from IPF cytokines. Most inflammatory diseases and disorders are lungs strongly express MMP-9. In addition, fibroblasts from characterized by abnormal accumulation of inflammatory patients with IPF express increased levels of all TIMPs. In this cells including monocytes/macrophages, granulocytes, setting, TIMPs may play a role in apoptosis in some cell plasma cells, lymphocytes and platelets. Along with tissue populations. In vitro studies of alveolar macrophages endothelial cells and fibroblasts, these inflammatory cells obtained from untreated patients with idiopathic pulmonary release a complex array of lipids, growth factors, cytokines fibrosis showed marked increase in MMP-9 secretion com and destructive enzymes that cause local tissue damage. pared to macrophages collected from healthy individuals. In 0067. One form of inflammatory response is neutrophilic animals models of bleomycin-induced pulmonary fibrosis inflammation which is characterized by infiltration of the MMPs have been shown to be elevated in bronchoalveolar inflamed tissue by neutrophil polymorphonuclear leukocytes lavage (BAL) fluid. Indeed, a synthetic inhibitor of MMP, (PMN), which are a major component of the host defense. Batimastat, has been shown to significantly reduce bleomy Tissue infection by extracellular bacteria represents the pro cin-induced lung fibrosis, again pointing to the importance of totype of this inflammatory response. On the other hand, MMPs in the development of this fibrotic disease in the lung. various non-infectious diseases are characterized by A number of studies have shown that the actions of MMPs can extravascular recruitment of neutrophils. This group of result in the release of growth factors and cytokines. These inflammatory diseases includes chronic obstructive pulmo profibrotic factors require proteolytic processing for their nary disease, adult respiratory distress syndrome, some types activation or release from extracellular matrix or carrier pro of immune-complex alveolitis, cystic fibrosis, bronchitis, teins before they can exert their activity. In fact, the pro bronchiectasis, emphysema, glomerulonephritis, rheumatoid teolytic activity processing of several key factors involved in arthritis, gouty arthritis, ulcerative colitis, certain dermatoses US 2010/0204152 A1 Aug. 12, 2010

Such as psoriasis and Vasculitis. In these conditions neutro Crohn's disease; Cushing's syndrome; dermatomyositis; dia phils are thought to play a crucial role in the development of betes mellitus; discoid lupus erythematosus; eosinophilic fas tissue injury which, when persistent, can lead to the irrevers ciitis; erythema nodosum: exfoliative dermatitis; fibromyal ible destruction of the normal tissue architecture with conse gia; focal glomerulosclerosis; focal segmental quent organ dysfunction. Tissue damage is primarily caused glomerulosclerosis; giant cell arteritis; gout; gouty arthritis; by the activation of neutrophils followed by their release of graft versus host disease; hand eczema, Henoch-Schonlein proteinases and increased production of oxygen species. purpura; herpes gestationis; hirsutism; idiopathic cerato 0068 Chronic obstructive pulmonary disease (COPD) is scleritis; idiopathic pulmonary fibrosis; idiopathic thromb described by the progressive development of airflow limita ocytopenic purpura; immune thrombocytopenic purpura tion that is not fully reversible. Most patients with COPD inflammatory bowel or gastrointestinal disorders, inflamma have three pathological conditions; bronchitis, emphysema tory dermatoses; lichen planus; lupus nephritis; lymphoma and mucus plugging. This disease is characterized by a slowly tous tracheobronchitis; macular edema; multiple Sclerosis: progressive and irreversible decrease in forced expiratory myasthenia gravis; myositis; nonspecific fibrosing lung dis volume in the first second of expiration (FEVi), with relative ease; osteoarthritis; pancreatitis; pemphigoid gestationis; preservation of forced vital capacity (FVC). In both asthma pemphigus Vulgaris; periodontitis; polyarteritis nodosa; and COPD there is significant, but distinct, remodeling of polymyalgia rheumatica; pruritus scroti; pruritis/inflamma airways. Most of the airflow obstruction is due to two major tion, psoriasis; psoriatic arthritis; pulmonary histoplasmosis: components, alveolar destruction (emphysema) and Small rheumatoid arthritis; relapsing polychondritis; rosacea airways obstruction (chronic obstructive bronchitis). COPD caused by sarcoidosis; rosacea caused by Scleroderma; rosa is mainly characterized by profound mucus cell hyperplasia. cea caused by Sweet's syndrome; rosacea caused by Systemic Neutrophil infiltration of the patient's lungs is a primary lupus erythematosus; rosacea caused by urticaria; rosacea characteristic of COPD. Elevated levels of proinflammatory caused by Zoster-associated pain; sarcoidosis; Scleroderma; cytokines, like TNF-C., and especially chemokines like inter segmental glomerulosclerosis; septic shock syndrome; leukin-8 (IL-8) and growth-regulated oncogene-C. (GRO-O.) shoulder tendinitis or bursitis; Sjogren's syndrome: Still's play a very important role in pathogenesis of this disease. disease; stroke-induced brain cell death; Sweet's disease; Platelet thromboxane synthesis is also enhanced in patients systemic lupus erythematosus; systemic Sclerosis; Takaya with COPD. Most of the tissue damage is caused by activation Su’s arteritis; temporal arteritis; toxic epidermal necrolysis; of neutrophils followed by their release of metalloprotein transplant-rejection and transplant-rejection-related Syn ases, and increased production of oxygen species. dromes; tuberculosis; type-1 diabetes; ulcerative colitis; 0069 TNF-C. has several biologic activities that are impor uveitis; vasculitis; and Wegener's granulomatosis. tant in homeostasis as well as in pathophysiological condi 0071. As used herein, “non-dermal inflammatory disor tions. The main sources of TNF-C. are monocytes-macroph ders' include, for example, rheumatoid arthritis, inflamma ages, T-lymphocytes and mast cells. The finding that anti tory bowel disease, asthma, and chronic obstructive pulmo TNF-C. antibodies (cA2) are effective in the treatment of nary disease. By “dermal inflammatory disorders' or patients suffering from rheumatoid arthritis (RA) intensified “inflammatory dermatoses’ is meant an inflammatory disor the interest to find new TNF-C. inhibitors as possible potent der selected from psoriasis, guttate psoriasis, inverse psoria medicaments for RA. Rheumatoid arthritis is an autoimmune sis, pustular psoriasis, erythrodermic psoriasis, acute febrile chronic inflammatory disease characterized by irreversible neutrophilic dermatosis, eczema, asteatotic eczema, pathological changes of the joints. In addition to RA, TNF-C. dyshidrotic eczema, Vesicular palmoplantar eczema, acne antagonists are also applicable to several other pathological Vulgaris, atopic dermatitis, contact dermatitis, allergic con conditions and diseases such as spondylitis, osteoarthritis, tact dermatitis, dermatomyositis, exfoliative dermatitis, hand gout and other arthritic conditions, sepsis, septic shock, toxic eczema, pompholyx, rosacea, rosacea caused by Sarcoidosis, shock syndrome, atopic dermatitis, contact dermatitis, pso rosacea caused by Scleroderma, rosacea caused by Sweet's riasis, glomerulonephritis, lupus erythematosus, Sclero syndrome, rosacea caused by Systemic lupus erythematosus, derma, asthma, cachexia, chronic obstructive lung disease, rosacea caused by urticaria, rosacea caused by Zoster-associ congestive heart failure, insulin resistance, lung (pulmonary) ated pain, Sweet's disease, neutrophilic hidradenitis, sterile fibrosis, multiple sclerosis, Crohn's disease, ulcerative coli pustulosis, drug eruptions, seborrheic dermatitis, pityriasis tis, viral infections and AIDS. rosea, cutaneous kikuchi disease, pruritic urticarial papules 0070 The term “immunoinflammatory disorder encom and plaques of pregnancy, Stevens-Johnson syndrome and passes a variety of conditions, including autoimmune dis toxic epidermal necrolysis, tattoo reactions, Wells syndrome eases, proliferative skin diseases, and inflammatory derma (eosinophilic cellulitis), reactive arthritis (Reiter's syn toses. Immunoinflammatory disorders result in the drome), bowel-associated dermatosis-arthritis syndrome, destruction of healthy tissue by an inflammatory process, rheumatoid neutrophilic dermatosis, neutrophilic eccrine dysregulation of the immune system, and unwanted prolif hidradenitis, neutrophilic dermatosis of the dorsal hands, bal eration of cells. Examples of immunoinflammatory disorders anitis circumscripta plasmacellularis, balanoposthitis, Beh are acne Vulgaris; acute respiratory distress syndrome: Addi cet's disease, erythema annulare centrifugum, erythema dys son's disease; allergic rhinitis; allergic intraocular inflamma chromicum perstans, erythema multiforme, granuloma tory diseases, antineutrophil cytoplasmic antibody (ANCA)- annulare, hand dermatitis, lichen nitidus, lichen planus, associated Small-vessel vasculitis; ankylosing spondylitis; lichen Sclerosus et atrophicus, lichen simplex chronicus, arthritis, asthma, atherosclerosis; atopic dermatitis; autoim lichen spinulosus, nummular dermatitis, pyoderma gan mune hepatitis; autoimmune hemolytic anemia; autoimmune grenosum, sarcoidosis, Subcorneal pustular dermatosis, urti hepatitis: Behcet’s disease; Bell's palsy; bullous pemphigoid; caria, and transient acantholytic dermatosis. cerebral ischemia; chronic obstructive pulmonary disease; 0072 By “proliferative skin disease' is meant a benign or cirrhosis: Cogan's syndrome; contact dermatitis: COPD; malignant disease that is characterized by accelerated cell US 2010/0204152 A1 Aug. 12, 2010 division in the epidermis or dermis. Examples of proliferative 0091 inflammation accompanying infection, such as sep skin diseases are psoriasis, atopic dermatitis, nonspecific der sis, septic shock, toxic shock syndrome:—fever, respiratory matitis, primary irritant contact dermatitis, allergic contact failure, tachycardia, hypotension, leukocytosis: dermatitis, basal and squamous cell carcinomas of the skin, 0092 other inflammatory conditions associated with par lamellar ichthyosis, epidermolytic hyperkeratosis, premalig ticular organs or tissues, such as: nant keratosis, acne, and seborrheic dermatitis. As will be 0093 (i) nephritis (e.g., glomeralonephritis):—oliguria, appreciated by one skilled in the art, a particular disease, abnormal urinalysis; disorder, or condition may be characterized as being both a 0094 (ii) inflamed appendix:—fever, pain, tenderness, proliferative skin disease and an inflammatory dermatosis. leukocytosis; An example of Such a disease is psoriasis. 0.095 (iii) gout: pain, tenderness, swelling and erythema 0073 Symptoms and signs of inflammation associated of the involved joint, elevated serum and/or urinary uric acid; with specific conditions include: 0096 (iv) inflamed gall bladder:—abdominal pain and 0074 rheumatoid arthritis: pain, swelling, warmth and tenderness, fever, nausea, leukocytosis: tenderness of the involved joints; generalized and morning 0097 (v) congestive heart failure:—shortness of breath, stiffness; rales, peripheral edema; 0075 insulin-dependent diabetes mellitus-insulitis; this 0.098 (vi) Type II diabetes:—end organ complications condition can lead to a variety of complications with an including cardiovascular, ocular, renal, and peripheral vascu inflammatory component, including:—retinopathy, neuropa lar disease; thy, nephropathy; coronary artery disease, peripheral vascu 0099 (vii) lung (pulmonary) fibrosis: hyperventilation, lar disease, and cerebrovascular disease; shortness of breath, decreased oxygenation; 0076 autoimmune thyroiditis: weakness, constipation, 0100 (viii) vascular disease, such as atherosclerosis and shortness of breath, puffiness of the face, hands and feet, restenosis: pain, loss of sensation, diminished pulses, loss peripheral edema, bradycardia; of function; and 0077 multiple sclerosis:—spasticity, blurry vision, ver 0101 (ix) alloimmunity leading to transplant rejection:— tigo, limb weakness, paresthesias; pain, tenderness, fever. 0078 uveoretinitis:—decreased night vision, loss of 0102) A human peptide is “active' in an inflammatory peripheral vision; disease if the inhibition is >50% in one of the assays described 0079 lupus erythematosus:- joint pain, rash, photosensi below. Inhibition (as percentage) was calculated using the tivity, fever, muscle pain, puffiness of the hands and feet, following formula: % inhibition (1-concentration of cytok abnormal urinalysis (hematuria, cylinduria, proteinuria), ines in Sample/concentration of cytokines in positive con glomerulonephritis, cognitive dysfunction, Vessel thrombo trol)x100. The positive control refers to stimulated samples, sis, pericarditis; not treated with substances. 0080 scleroderma:—Raynaud's disease; swelling of the 0103) The peptide or the peptide combination of the hands, arms, legs and face; skin thickening; pain, Swelling present invention were tested using the assays described in and stiffness of the fingers and knees, gastrointestinal dys Examples 1-7, 9-17 for their effect as active therapeutic function, restrictive lung disease; pericarditis; renal failure; agents in the prophylaxis and/or treatment of inflammatory 0081 other arthritic conditions having an inflammatory diseases and disorders. component such as rheumatoid spondylitis, osteoarthritis, 0104 Neurodegenerative Disease septic arthritis and polyarthritis:—fever, pain, Swelling, ten 0105. The present invention also relates generally to the derness; fields of neurology and psychiatry and to methods of protect 0082 other inflammatory brain disorders, such as menin ing the cells of a mammalian central nervous system from gitis, Alzheimer's disease, AIDS dementia encephalitis:— damage or injury. photophobia, cognitive dysfunction, memory loss; 0106 Injuries or trauma of various kinds to the central 0083 other inflammatory eye inflammations, such as nervous system (CNS) or the peripheral nervous system retinitis:—decreased visual acuity; (PNS) can produce profound and long-lasting neurological 0084 inflammatory skin disorders, such as, eczema, other and/or psychiatric symptoms and disorders. One form that dermatites (e.g., atopic, contact), psoriasis, burns induced by this can take is the progressive death of neurons or other cells UV radiation (Sun rays and similar UV sources):—erythema, of the central nervous system (CNS), i.e., neurodegeneration pain, Scaling, Swelling, tenderness; or neuronal degeneration. 0107 Neuronal degeneration as a result of for example: 0085 inflammatory bowel disease, such as Crohn's dis Alzheimer's disease, multiple Sclerosis, cerebral-vascular ease, ulcerative colitis: pain, diarrhea, constipation, rectal accidents (CVAS)/stroke, traumatic brain injury, spinal cord bleeding, fever, arthritis; injuries, degeneration of the optic nerve, e.g., ischemic optic I0086 asthma:—shortness of breath, wheezing: neuropathy or retinal degeneration and other central nervous 0087 other allergy disorders, such as allergic rhinitis:— system disorders is an enormous medical and public health Sneezing, itching, runny nose problem by virtue of both its high incidence and the frequency 0088 conditions associated with acute trauma such as of long-term sequelae. Animal studies and clinical trials have cerebral injury following stroke-sensory loss, motor loss, shown that amino acid transmitters (especially glutamate), cognitive loss; oxidative stress and inflammatory reactions contribute 0089 heart tissue injury due to myocardial ischemia:— strongly to cell deathin these conditions. Upon injury or upon pain, shortness of breath; ischemic insult, damaged neurons release massive amounts 0090 lung injury such as that which occurs in adult respi of the neurotransmitter glutamate, which is excitotoxic to the ratory distress syndrome:—shortness of breath, hyperventi Surrounding neurons. Glutamate is a negatively charged lation, decreased oxygenation, pulmonary infiltrates; amino acid that is an excitatory synaptic transmitter in the US 2010/0204152 A1 Aug. 12, 2010

mammalian nervous system. Although the concentration of ders, including but not limited to, progressive, deteriorating glutamate can reach the millimolar range in nerve terminals forms of bipolar disorder or schizoaffective disorder or its extracellular concentration is maintained at a low level to Schizophrenia, impulse control disorders, obsessive compul prevent neurotoxicity. It has been noted that glutamate can be sive disorder (OCD), behavioral changes in temporal lobe toxic to neurons if presented at a high concentration. The term epilepsy and personality disorders. “excitotoxicity' has been used to describe the cytotoxic effect 0112. In one preferred embodiment the compounds of the that glutamate (and other Such excitatory amino acids) can invention would be used to provide neuroprotection in disor have on neurons when applied at high dosages. ders involving trauma and progressive injury to the nervous 0108 Patients with injury or damage of any kind to the system in various psychiatric disorders. These disorders central (CNS) or peripheral (PNS) nervous system including would be selected from the group consisting of Schizoaffec the retina may benefit from neuroprotective methods. This tive disorder, Schizophrenia, impulse control disorders, nervous system injury may take the form of anabrupt insult or obsessive compulsive disorder (OCD) and personality disor an acute injury to the nervous system as in, for example, acute ders. neurodegenerative disorders including, but not limited to: 0113. In addition, trauma and injury make take the form of acute injury, hypoxia-ischemia or the combination thereof disorders associated with overt and extensive memory loss resulting in neuronal cell death or compromise. Acute injury including, but not limited to, neurodegenerative disorders includes, but is not limited to, traumatic brain injury (TBI) associated with age-related dementia, Vascular dementia, dif including, closed, blunt or penetrating brain trauma, focal fuse white matter disease (Binswanger's disease), dementia brain trauma, diffuse brain damage, spinal cord injury, intrac of endocrine or metabolic origin, dementia of head trauma ranial or intravertebral lesions (including, but not limited to, and diffuse brain damage, dementia pugilistica or frontal lobe contusion, penetration, shear, compression or laceration dementia, including but not limited to Pick's Disease. lesions of the spinal cord or whiplash shaken infant Syn 0114. Other disorders associated with neuronal injury drome). include, but are not limited to, disorders associated with 0109. In addition, deprivation of oxygen or blood supply chemical, toxic, infectious and radiation injury of the nervous in general can cause acute injury as in hypoxia and/or system including the retina, injury during fetal development, ischemia including, but not limited to, cerebrovascular insuf prematurity at time of birth, anoxic-ischemia, injury from ficiency, cerebral ischemia or cerebral infarction (including hepatic, glycemic, uremic, electrolyte and endocrine origin, cerebral ischemia or infarctions originating from embolic injury of psychiatric origin (including, but not limited to, occlusion and thrombosis, retinal ischemia (diabetic or oth psychopathology, depression or anxiety), injury from periph erwise), glaucoma, retinal degeneration, multiple Sclerosis, eral diseases and plexopathies (including plexus palsies) or toxic and ischemic optic neuropathy, reperfusion following injury from neuropathy (including neuropathy selected from acute ischemia, perinatal hypoxic-ischemic injury, cardiac multifocal, sensory, motor, sensory-motor, autonomic, sen arrest or intracranial hemorrhage of any type (including, but sory-autonomic or demyelinating neuropathies (including, not limited to, epidural, Subdural, Subarachnoid or intracere but not limited to Guillain-Barre syndrome or chronic inflam bral hemorrhage). matory demyelinating polyradiculoneuropathy) or those neu 0110 Trauma or injury to tissues of the nervous system ropathies originating from infections, inflammation, immune may also take the form of more chronic and progressive disorders, drug abuse, pharmacological treatments, toxins, neurodegenerative disorders, such as those associated with trauma (including, but not limited to compression, crush, progressive neuronal cell death or compromise over a period laceration or segmentation traumas), metabolic disorders (in of time including, but not limited to, Alzheimer's disease, cluding, but not limited to, endocrine or paraneoplastic), Pick's disease, diffuse Lewy body disease, progressive Supra Charcot-Marie-Tooth disease (including, but not limited to, nuclear palsy (Steel-Richardson syndrome), multisystem type 1a, 1b, 2, 4a or 1-X linked), Friedreich's ataxia, metach degeneration (Shy-Drager syndrome), chronic epileptic con romatic leukodystrophy, RefSum's disease, adrenomyelo ditions associated with neurodegeneration, motor neuron dis neuropathy, ataxia-telangiectasia, Djerine-Sottas (including, eases (amyotrophic lateral Sclerosis), multiple Sclerosis, but not limited to, types A or B), Lambert-Eaton syndrome or degenerative ataxias, cortical basal degeneration, ALS-Par disorders of the cranial nerves). kinson’s-dementia complex of Guam, Subacute Sclerosing 0115 Further indications are cognitive disorders. The panencephalitis, Huntington's disease, Parkinson's disease, term “cognitive disorder shall refer to anxiety disorders, Synucleinopathies (including multiple system atrophy), pri delirium, dementia, amnestic disorders, dissociative disor mary progressive aphasia, striatonigral degeneration, ders, eating disorders, mood disorders, Schizophrenia, psy Machado-Joseph disease or spinocerebellar ataxia type 3 and chotic disorders, sexual and gender identity disorders, sleep olivopontocerebellardegenerations, bulbar and pseudobulbar disorders, Somatoform disorders, acute stress disorder, obses palsy, spinal and spinobulbar muscular atrophy (Kennedy's sive-compulsive disorder, panic disorder, posttraumatic disease), primary lateral Sclerosis, familial spastic paraplegia, stress disorder, specific phobia, Social phobia, Substance Werdnig-Hoffmann disease, Kugelberg-Welander disease, withdrawal delirium, Alzheimer's disease, Creutzfeldt-Jakob Tay-Sach's disease, Sandhoff disease, familial spastic dis disease, head trauma, Huntington's disease, HIV disease, ease, Wohlfart-Kugelberg-Welander disease, spastic para Parkinson's disease, Pick's disease, learning disorders, motor paresis, progressive multifocal leukoencephalopathy, famil skills disorders, developmental coordination disorder, com ial dysautonomia (Riley-Day Syndrome) or prion diseases munication disorders, phonological disorder, pervasive (including, but not limited to Creutzfeld-Jakob disease, Ger developmental disorders, Asperger's disorder, autistic disor stmann-Strussler-Scheinker disease, Kuru disease or fatal der, childhood disintegrative disorder, Rett's disorder, perva familial insomnia). sive developmental disorder, attention-deficit/hyperactivity 0111. In addition, trauma and progressive injury to the disorder (ADHD), conduct disorder, oppositional defiant dis nervous system can take place in various psychiatric disor order, pica, rumination disorder, tic disorders, chronic motor US 2010/0204152 A1 Aug. 12, 2010

or vocal tic disorder, Tourette's disorder, elimination disor dine-related disorder, abuse, persisting amnestic disorder, ders, encopresis, enuresis, selective mutism, separation anxi anxiety disorder, persisting dementia, dependence, intoxica ety disorder, dissociative amnesia, depersonalization disor tion, intoxication delirium, mood disorder, psychotic disor der, dissociative fugue, dissociative identity disorder, der, withdrawal, withdrawal delirium, sexual dysfunction, anorexia nervosa, bulimia nervosa, bipolar disorders, Schizo sleep disorder. phreniform disorder, schizoaffective disorder, delusional dis 0119 The term “neuroprotection” as used herein shall order, psychotic disorder, shared psychotic disorder, delu mean: inhibiting, preventing, ameliorating or reducing the sions, hallucinations, Substance-induced psychotic disorder, severity of the dysfunction, degeneration or death of nerve orgasmic disorders, sexual pain disorders, dyspareunia, cells, axons or their supporting cells in the central or periph vaginismus, sexual dysfunction, paraphilias, dyssomnias, eral nervous system of a mammal, including a human. This breathing-related sleep disorder, circadian rhythm sleep dis includes the treatment or prophylaxis of a neurodegenerative order, hypersomnia, insomnia, narcolepsy, dyssomnia, para disease; protection against excitotoxicity or ameliorating the Somnias, nightmare disorder, sleep terror disorder, sleep cytotoxic effect of a compound (for example, a excitatory walking disorder, parasomnia, body dysmorphic disorder, amino acid Such as glutamate; a toxin; or a prophylactic or conversion disorder, hypochondriasis, pain disorder, Somati therapeutic compound that exerts an immediate or delayed Zation disorder, alcohol related disorders, amphetamine cytotoxic side effect including but not limited to the immedi related disorders, caffeine related disorders, cannabis related ate or delayed induction of apoptosis) in a patient in need disorders, cocaine related disorders, hallucinogen related dis thereof. orders, inhalant related disorders, nicotine related disorders, 0.120. The term “a patient in need of treatment with a opioid related disorders, phencyclidine-related disorder, neuroprotective drug” as used herein will refer to any patient abuse, persisting amnestic disorder, intoxication, withdrawal. who currently has or may develop any of the above Syn 0116. The term “bipolar and clinical disorders' shall refer dromes or disorders, or any disorder in which the patient's to adjustment disorders, anxiety disorders, delirium, demen present clinical condition or prognosis could benefit from tia, amnestic and other cognitive disorders, disorders usually providing neuroprotection to prevent the development, exten first diagnosed in infancy (e.g.), childhood, or adolescence, Sion, worsening or increased resistance to treatment of any dissociative disorders (e.g. dissociative amnesia, depersonal neurological or psychiatric disorder. ization disorder, dissociative fugue and dissociative identity I0121 The term “treating or “treatment as used herein, disorder), eating disorders, factitious disorders, impulse-con refers to any indicia of Success in the prevention or amelio trol disorders, mental disorders due to a general medical ration of an injury, pathology or condition, including any condition, mood disorders, other conditions that may be a objective or subjective parameter Such as abatement; remis focus of clinical attention, personality disorders, Schizophre sion; diminishing of symptoms or making the injury, pathol nia and other psychotic disorders, sexual and gender identity ogy, or condition more tolerable to the patient; slowing in the disorders, sleep disorders. Somatoform disorders, Substance rate of degeneration or decline; making the final point of related disorders, generalized anxiety disorder (e.g. acute degenerationless debilitating; or improving a subject's physi stress disorder, posttraumatic stress disorder), panic disorder, cal or mental well-being. The treatment or amelioration of phobia, agoraphobia, obsessive-compulsive disorder, stress, symptoms can be based on objective or Subjective param acute stress disorder, anxiety neurosis, nervousness, phobia, eters; including the results of a physical examination, neuro posttraumatic stress disorder, posttraumatic stress disorder logical examination, and/or psychiatric evaluations. (PTSD), abuse, obsessive-compulsive disorder (OCD), I0122. In some embodiments this invention provides meth manic depressive psychosis, specific phobias, social phobia, ods of neuroprotection. In certain embodiments, these meth adjustment disorder with anxious features. ods comprise administering a therapeutically effective 0117 Examples for disorders usually first diagnosed in amount of the peptide combination of the invention to a infancy, childhood, or adolescence are: mental retardation, patient who has not yet developed overt, clinical signs or learning disorders, mathematics disorder, reading disorder, symptoms of injury or damage to the cells of the nervous disorder of written expression, motor skills disorders, devel system but who may be in a high risk group for the develop opmental coordination disorder, communication disorders, ment of neuronal damage because of injury or trauma to the expressive language disorder, phonological disorder, mixed nervous system or because of some known predisposition receptive-expressive language disorder, Stuttering, pervasive either biochemical or genetic or the finding of a verified developmental disorders, Asperger's disorder, autistic disor biomarker of one or more of these disorders. der, childhood disintegrative disorder, Rett's disorder, perva (0123 Thus, in some embodiments, the methods and com sive developmental disorder, attention-deficit/hyperactivity positions of the present invention are directed toward neuro disorder (ADHD), conduct disorder, oppositional defiant dis protection in a subject who is at risk of developing neuronal order, feeding disorder of infancy or early childhood, pica, damage but who has not yet developed clinical evidence. This rumination disorder, tic disorders, chronic motor or vocal tic patient may simply be at “greater risk” as determined by the disorder, Tourette's syndrome, elimination disorders, enco recognition of any factor in a Subjects, or their families, presis, enuresis, selective mutism, separation anxiety disor medical history, physical exam or testing that is indicative of der, reactive attachment disorder of infancy or early child a greater than average risk for developing neuronal damage. hood, stereotypic movement disorder. Therefore, this determination that a patient may be at a 0118. Examples for substance-related disorders are: alco “greater risk” by any available means can be used to deter hol related disorders, amphetamine related disorders, caf mine whether the patient should be treated with the methods feine related disorders, cannabis related disorders, cocaine of the present invention. related disorders, hallucinogen related disorders, inhalant 0.124. Accordingly, in an exemplary embodiment, Subjects related disorders, nicotine related disorders, opioid related who may benefit from treatment by the methods and the disorders, psychotic disorder, psychotic disorder, phencycli peptide or the peptide combination of this invention can be US 2010/0204152 A1 Aug. 12, 2010 identified using accepted Screening methods to determine risk toms and psychotic symptoms over time and in relation to factors for neuronal damage. These screening methods other treatments the patient may have received over time, e.g., include, for example, conventional work-ups to determine a life chart. These and other specialized and routine methods risk factors including but not limited to: for example, head allow the clinician to select patients in need of therapy using trauma, either closed or penetrating, CNS infections, bacte the methods and formulations of this invention. In some rial or viral, cerebrovascular disease including but not limited embodiments of the present invention peptides suitable for to stroke, brain tumors, brainedema, cysticercosis, porphyria, use in the practice of this invention will be administered either metabolicencephalopathy, drug withdrawal including but not singly or concomitantly with at least one or more other com limited to sedative-hypnotic or alcohol withdrawal, abnormal pounds ortherapeutic agents, e.g., with other neuroprotective perinatal history including anoxia at birth or birth injury of any kind, cerebral palsy, learning disabilities, hyperactivity, drugs or antiepileptic drugs, anticonvulsant drugs. In these history of febrile convulsions as a child, history of status embodiments, the present invention provides methods to treat epilepticus, family history of epilepsy or any seizure related or prevent neuronal injury in a patient. The method includes disorder, inflammatory disease of the brain including lupis, the step of administering to a patient in need of treatment, an drug intoxication either director by placental transfer, includ effective amount of one of the peptides disclosed herein in ing but not limited to cocaine poisoning, parental consanguin combination with an effective amount of one or more other ity, and treatment with medications that are toxic to the ner compounds or therapeutic agents that have the ability to pro Vous system including psychotropic medications. vide neuroprotection or to treat or prevent seizures or epilep 0.125. The determination of which patients may benefit togenesis or the ability to augment the neuroprotective effects from treatment with a neuroprotective drug in patients who of the compounds of the invention. have no clinical signs or symptoms may be based on a variety 0129. As used herein the term “combination administra of “surrogate markers' or “biomarkers’. tion of a compound, therapeutic agent or known drug with 0126. As used herein, the terms “surrogate marker” and the peptide combination of the present invention means “biomarker are used interchangeably and refer to any ana administration of the drug and the one or more compounds at tomical, biochemical, structural, electrical, genetic or chemi such time that both the known drug and the peptide combi cal indicator or marker that can be reliably correlated with the nation will have a therapeutic effect. In some cases this thera present existence or future development of neuronal damage. peutic effect will be synergistic. Such concomitant adminis In some instances, brain-imaging techniques, such as com tration can involve concurrent (i.e. at the same time), prior, or puter tomography (CT), magnetic resonance imaging (MRI) subsequent administration of the drug with respect to the or positron emission tomography (PET), can be used to deter administration of the peptide combination of the present mine whether a Subject is at risk for neuronal damage. Suit invention. A person of ordinary skill in the art would have no able biomarkers for the methods of this invention include, but difficulty determining the appropriate timing, sequence and are not limited to: the determination by MRI, CT or other dosages of administration for particular drugs and peptides of imaging techniques, of Sclerosis, atrophy or Volume loss in the present invention. the hippocampus or overt mesial temporal sclerosis (MTS) or 0.130. The said one or more other compounds or therapeu similar relevant anatomical pathology; the detection in the tic agents may be selected from compounds that have one or patient's blood, serum or tissues of a molecular species Such more of the following properties: antioxidant activity; as a protein or other biochemical biomarker, e.g., elevated NMDA receptor antagonist activity, augmentation of endog levels of ciliary neurotrophic factor (CNTF) or elevated enous GABA inhibition: NO synthase inhibitor activity; iron serum levels of a neuronal degradation product; or other binding ability, e.g., an iron chelator, calcium binding ability, evidence from Surrogate markers or biomarkers that the e.g., a Ca (II) chelator; Zinc binding ability, e.g., a Zn (II) patient is in need of treatment with a neuroprotective drug. chelator; the ability to effectively block sodium or calcium 0127. It is expected that many more such biomarkers uti ion channels, or to open potassium or chloride ion channels in lizing a wide variety of detection techniques will be devel the CNS of a patient. oped in the future. It is intended that any such marker or indicator of the existence or possible future development of I0131 The peptide or the peptide combination of the neuronal damage, as the latter term is used herein, may be present invention were tested using the assays described in used in the methods of this invention for determining the need Examples 1-7, 9-17 for their effect as active therapeutic for treatment with the compounds and methods of this inven agents in the prophylaxis and/or treatment of neurodegenera tion. tive diseases and disorders. 0128. A determination that a subject has, or may be at risk (0132 Heart and Vascular Disease for developing, neuronal damage would also include, for 0.133 Heart disease is a general term used to describe example, a medical evaluation that includes a thorough his many different heart conditions. tory, a physical examination, and a series of relevant bloods I0134) For example, coronary artery disease, which is the tests. It can also include an electroencephalogram (EEG), CT, most common heart disease, is characterized by constriction MRI or PET scan. A determination of an increased risk of or narrowing of the arteries Supplying the heart with oxygen developing neuronal damage or injury may also be made by rich blood, and can lead to myocardial infarction, which is the means of genetic testing, including gene expression profiling death of a portion of the heart muscle. Heart failure is a or proteomic techniques. For psychiatric disorders that may condition resulting from the inability of the heart to pump an be stabilized or improved by a neuroprotective drug, e.g., adequate amount of blood through the body. Heart failure is bipolar disorder, schizoaffective disorder, schizophrenia, not a Sudden, abrupt stop of heart activity but, rather, typically impulse control disorders, etc. the above tests may also develops slowly over many years, as the heart gradually loses include a present state exam and a detailed history of the its ability to pump blood efficiently. Risk factors for heart course of the patients symptoms Such as mood disorder Symp failure include coronary artery disease, hypertension, Valvu US 2010/0204152 A1 Aug. 12, 2010

lar heart disease, cardiomyopathy, disease of the heart 0.139. Peripheral vascular disease is also manifested in muscle, obesity, diabetes, and/or a family history of heart atherosclerotic stenosis of the renal artery, which can lead to failure. renal ischemia and kidney dysfunction. 0135 Examples of cardiovascular diseases and disorders 0140. One disease in which vascular diseases and their are: aneurysm, stable angina, unstable angina, angina pecto complications are very common is diabetes mellitus. Diabe tes mellitus causes a variety of physiological and anatomical ris, angioneurotic edema, aortic valve Stenosis, aortic aneu irregularities, the most prominent of which is the inability of rysm, arrhythmia, arrhythmogenic right ventricular dyspla the body to utilize glucose normally, which results in hyper sia, arteriosclerosis, arteriovenous malformations, atrial glycemia. Chronic diabetes can lead to complications of the fibrillation, Behcet syndrome, bradycardia, cardiac tampon vascular system which include atherosclerosis, abnormalities ade, cardiomegaly, congestive cardiomyopathy, hypertrophic involving large and medium size blood vessels (macroangi cardiomyopathy, restrictive cardiomyopathy, carotid Steno opathy) and abnormalities involving Small blood vessels (mi sis, cerebral hemorrhage, Churg-Strauss syndrome, diabetes, croangiopathy) Such as arterioles and capillaries. Ebstein's Anomaly, Eisenmenger complex, cholesterol 0.141. Patients with diabetes mellitus are at increased risk embolism, bacterial endocarditis, fibromuscular dysplasia, of developing one or more foot ulcers as a result of established congenital heart defects, heart diseases, congestive heart fail long-term complications of the disease, which include ure, heart Valve diseases, heart attack, epidural hematoma, impaired nerve function (neuropathy) and/or ischemia. Local hematoma, Subdural, Hippel-Lindau disease, hyperemia, tissue ischemia is a key contributing factor to diabetic foot hypertension, pulmonary hypertension, cardiac hypertrophy, ulceration. left ventricular hypertrophy, right ventricular hypertrophy, 0142. In addition to large vessel disease, patients with hypoplastic left heart syndrome, hypotension, intermittent diabetes suffer further threat to their skin perfusion in at least claudication, ischemic heart disease, Klippel-Trenaunay-We two additional ways. First, by involvement of the non-conduit ber syndrome, lateral medullary syndrome, long QT syn arteries, which are detrimentally affected by the process of drome mitral valve prolapse, moyamoya disease, mucocuta atherosclerosis, and secondly, and perhaps more importantly, neous lymph node syndrome, myocardial infarction, by impairment of the microcirculatory control mechanisms myocardial ischemia, myocarditis, pericarditis, peripheral (small vessel disease). Normally, when a body part suffers vascular diseases, phlebitis, polyarteritis nodosa, pulmonary some form of trauma, the body part will, as part of the body's atresia, Raynaud disease, Sneddon syndrome, Superior Vena healing mechanism, experience an increased blood flow. cava syndrome, syndrome X, tachycardia, Takayasu's arteri When small vessel disease and ischemia are both present, as tis, hereditary hemorrhagic telangiectasia, telangiectasis, in the case of many diabetics, this natural increased blood temporal arteritis, tetralogy of Fallot, thromboangiitis oblit flow response is significantly reduced. This fact, together erans, thrombosis, thromboembolism, tricuspidatresia, Vari with the tendency of diabetics to form blood clots (thrombo cose veins, vascular diseases, vasculitis, vasospasm, ven sis) in the microcirculatory system during low levels of blood tricular fibrillation, Williams syndrome, peripheral vascular flow, is believed to be an important factor in ulcer pathogen disease, varicose veins and leg ulcers, deep vein thrombosis, CS1S. Wolff-Parkinson-White syndrome. 0.143 Neuropathy is a general term which describes a 0136 Vascular diseases are often the result of decreased disease process which leads to the dysfunction of the nervous perfusion in the vascular system or physical or biochemical system, and is one of the major complications of diabetes injury to the blood vessel. mellitus, with no well-established therapies for either its 0137 Peripheral vascular disease (PVD) is defined as a symptomatic treatment or for prevention of progressive disease of blood vessels often encountered as narrowing of decline in nerve function. the vessels of the limbs. There are two main types of these 0144. The thickening and leakage of capillaries caused by disorders, functional disease which doesn't involve defects in diabetes primarily affect the eyes (retinopathy) and kidneys the blood vessels but rather arises from stimuli such as cold, (nephropathy). The thickening and leakage of capillaries stress, or Smoking, and organic disease which arises from caused by diabetes are also associated with skin disorders and structural defects in the vasculature Such as atherosclerotic disorders of the nervous system (neuropathy). lesions, local inflammation, or traumatic injury. This can lead 0145 The eye diseases associated with diabetes are non to occlusion of the vessel, aberrant blood flow, and ultimately proliferative diabetic retinopathy, proliferative diabetic retin to tissue ischemia. opathy, diabetic maculopathy, glaucoma, cataracts and the 0.138. One of the more clinically significant forms of PVD like. is peripheral artery disease (PAD). PAD is often treated by 0146. Other diseases, although not known to be related to angioplasty and implantation of a stent or by artery bypass diabetes are similar in their physiological effects on the Surgery. Clinical presentation depends on the location of the peripheral vascular system. Such diseases include Raynaud occluded vessel. For example, narrowing of the artery that syndrome, CREST syndrome, autoimmune diseases Such as Supplies blood to the intestine can result in severe postpran erythematosis, rheumatoid disease, and the like. dial pain in the lower abdomen resulting from the inability of 0147 As used herein, the term “peripheral vascular dis the occluded vessel to meet the increased oxygen demand eases’ comprises any peripheral vascular disease including arising from digestive and absorptive processes. In severe peripheral and autonomic neuropathies. Examples of forms the ischemia can lead to intestinal necrosis. Similarly, “peripheral vascular disease' include peripheral arterial dis PAD in the leg can lead to intermittent pain, usually in the ease, such as chronic arterial occlusion including arterioscle calf, that comes and goes with activity. This disorder is known rosis, arteriosclerosis obliterans and thromboangiitis obliter as intermittent claudication (IC) and can progress to persis ans (Buerger's disease), macroangiopathy, microangiopathy, tent pain while resting, ischemic ulceration, and even ampu diabetes mellitus, thrombophlebitis, phlebemphraxis, tation. Raynaud's disease, Raynaud's syndrome, CREST syndrome, US 2010/0204152 A1 Aug. 12, 2010

health hazard due to vibration, Sudeck's syndrome, intermit integrins. These sprouts then form loops to become a full tent claudication, cold sense in extremities, abnormal sensa fledged vessel lumen as cells migrate to the site of angiogen tion in extremities, sensitivity to the cold, Meniere's disease, esis. Sprouting occurs at a rate of several millimeters per day, Meniere's syndrome, numbness, lack of sensation, anesthe and enables new vessels to grow across gaps in the vascula sia, resting pain, causalgia (burning pain), disturbance of ture. peripheral circulation function, disturbance of nerve func 0152 Therapeutic angiogenesis is the application of spe tion, disturbance of motor function, motor paralysis, diabetic cific compounds which may inhibit or induce the creation of peripheral circulation disorder, lumbar spinal canal Stenosis, new blood vessels in the body in order to combat disease. The diabetic neuropathy, shock, autoimmune disease Such as presence of blood vessels where there should be none may erythematosis, rheumatoid disease and rheumatoid arthritis, affect the mechanical properties of a tissue, increasing the autonomic neuropathy, diabetic autonomic neuropathy, auto likelihood of failure. The absence of blood vessels in a repair nomic imbalance, orthostatic hypotension, erectile dysfunc ing or otherwise metabolically active tissue may retard repair tion, female sexual dysfunction, retrograde ejaculation, cys or some other function. Several diseases are the result of topathy, neurogenic bladder, defective vaginal lubrication, failure or insufficient blood vessel formation and may be exercise intolerance, cardiac denervation, heat intolerance, treated by a local expansion of blood vessels, thus bringing gustatory Sweating, diabetic complication, hyperglycemia, new nutrients to the site, facilitating repair. Other diseases hypoglycemia unawareness, hypoglycemia unresponsive may be created by a local expansion of blood vessels, inter ness; glaucoma, neovascular glaucoma, cataract, retinopathy, fering with normal physiological processes. diabetic retinopathy, diabetic maculopathy, occlusion of reti 0153. Angiogenesis represents an excellent therapeutic nal artery, obstruction of central artery of retina, occlusion of target for the treatment of for example, cardiovascular dis retinal vein, macular edema, aged macular degeneration, eases. It is a potent, physiological process that underlies the aged disciform macular degeneration, cystoid macular natural manner in which the human body responds to a dimi edema, palpebral edema, retinal edema, chorioretinopathy, nution of blood Supply to vital organs, namely the production neovascular maculopathy, uveitis, iritis, retinal vasculitis, of new collateral vessels to overcome the ischemic insult. endophthalmitis, panophthalmitis, metastatic ophthalmia, 0154 The modern clinical application of the principle choroiditis, retinal pigment epithelitis, conjunctivitis, cycli “angiogenesis' can be divided into two main areas: tis, Scleritis, episcleritis, optic neuritis, retrobulbar optic neu 0155 1. Anti-angiogenic therapies ritis, keratitis, blepharitis, exudative retinal detachment, cor 0156 2. Pro-angiogenic therapies. neal ulcer, conjunctival ulcer, chronic nummular keratitis, (O157. Whereas anti-angiogenic therapies are trying to Thygeson keratitis, progressive Mooren's ulcer, damage of fight: skin, skin ulcer including foot ulcer, diabetic ulcer, burn ulcer, 0158 Any type of cancer and malignancies and their lower leg ulcer, postoperative ulcer, traumatic ulcer, ulcer metastases in numerous organs, like hemangiomas (be after herpes Zoster, radiation ulcer, drug induced ulcer, frost cause tumors, in general, are nutrition- and oxygen bite (cold injury), chilblain, gangrene and Sudden gangrene, dependent, thus being in need of adequate blood Sup angina pectoris/variant angiitis, coronary arteriosclerosis ply), (chronic ischemic heart disease, asymptomatic ischemic 0159. Infectious diseases, heart disease, arteriosclerotic cardiovascular disease), myo 0160 Vasculitis and excessive angiogenesis in autoim cardial infarction, heart failure, congestive heart failure and mune disorders such as systemic sclerosis (Sclero painless ischemic heart disease, pulmonary edema, hyperten derma), multiple Sclerosis, Sjögren's disease, Sion, pulmonary hypertension; portal hypertension, diabetic 0.161 Vascular malformations in blood and lymph ves nephropathy, decubitus, renal failure. sels like DiGeorge syndrome, hereditary haemorrhagic 0148. The peptide or the peptide combination of the telangiectasia, cavernous hemangioma, cutaneous present invention were tested using the assays described in hemangioma, lymphatic malformations, transplantarte Examples 1-7, 9-17 for their effect as active therapeutic riopathy, atherosclerosis, vascular anastomoses, agents in the prophylaxis and/or treatment of heart and vas 0162 Adipose tissue in obesity, cular diseases. 0.163 Chronic allograft rejections, 0149 Angiogenesis 0164. Skin diseases like psoriasis, warts, allergic der 0150 Angiogenesis is a physiological process involving matitis, Scar keloids, pyogenic granulomas, blistering the growth of new blood vessels from pre-existing vessels. disease, Kaposi sarcoma in AIDS patients, systemic Angiogenesis is a normal process in growth and development, Sclerosis (Scleroderma), as well as in wound healing. However, this is also a funda 0.165 Eye diseases like persistent hyperplastic vitreous mental step in the transition of tumors from a dormant state to syndrome, diabetic retinopathy, retinopathy of prematu a malignant state. rity, choroidal neovascularization, 0151. Angiogenesis occurs in several well-characterized 0166 Lung diseases like any type of pulmonary hyper stages. First, biological signals known as angiogenic growth tension, asthma, nasal polyps, rhinitis, chronic airway factors activate receptors present on endothelial cells present inflammation and obstruction (COPD), cystic fibrosis, in pre-existing blood vessels. Second, the activated endothe acute lung injury, bronchiolitis obliterans organizing lial cells begin to release enzymes called proteases that pneumonia, degrade the basement membrane in order to allow endothelial 0.167 Gastrointestinal tract diseases like inflammatory cells to escape from the original (parent) vessel walls. The bowel disease, periodontal disease, ascites, peritoneal endothelial cells then proliferate into the surrounding matrix adhesions, liver cirrhosis, and form Solid sprouts connecting neighboring vessels. As 0168 Reproductive system diseases like endometrio sprouts extend toward the Source of the angiogenic stimulus, sis, uterine bleeding, ovarian cysts, ovarian hyperstimu endothelial cells migrate, using adhesion molecules, called lation, US 2010/0204152 A1 Aug. 12, 2010 14

0169 Bone and joint diseases like arthritis and synovi In these cases, the most common form of treatment has been tis, osteomyelitis, osteophyte formation, HIV-induced the use of synthetic polymeric materials, like ePTFE (ex bone marrow angiogenesis, tended polytetrafluoroethylene) and Dacron (polyethylene 0170 Kidney diseases like early diabetic nephropathy terephthalate), to form either permanent or resorbable 0171 The pro-angiogenic therapies are important in the replacements for the damaged vessels. In cases where the search of new treatment options for diseases characterized or graft can be of a large diameter (greater than 5-6 mm), the caused by insufficient angiogenesis or vessel regression: synthetic material has been effective. However, in situations 0172 Nervous system diseases like Alzheimer's dis where a smaller vessel diameter is required, the synthetic ease, amyotrophic lateral sclerosis, diabetic neuropathy, stroke, materials cannot be used due to high rates of Stenosis and 0173 Blood and lymph vessels diseases like diabetic thrombus formation. One possible solution is to use natural angiopathy, impared reendothelialization in restenosis, materials like collagen, either modified or combined with a lymphedema, synthetic material, to form a graft that more closely mimics 0.174 Gastrointestinal ulcerations, oral ulcers, mucosal the body's natural function and has low thrombogenicity and ischemia in Crohn's disease low incidence of Stenosis. 0.175 Skin diseases like lupus, 0185. Failure of the autograft is usually due to some form 0176 Reproductive system diseases like preeclampsia, of occlusion that results from lumenal narrowing. Damage of menorrhagia, the vessel during removal and reimplantation may cause the 0177 Lung diseases like neonatal respiratory distress recruitment of factors or cells that adhere to the autograft wall syndrome, pulmonary fibrosis, emphysema, and decrease the diameter of the lumen. The restricted flow 0.178 Kidney diseases like nephropathy, glomerulo then increases the thrombogenicity, making full occlusion sclerosis, tubulointerstitial fibrosis, even more likely. Other problems are preparation and preser 0179 Bone diseases like osteoporosis, impaired bone Vation of the autograft, procedures that can result in vessel fracture healing, damage or diminished in vivo performance. Finally, due to 0180 Heart diseases like ischaemic heart disease, car increased and/or different mechanical forces, endothelial diac failure, cells can shrink, diminishing barrier performance, and 0181 Any type of wound healing disorders. degrade, also resulting in increased thrombogenicity. In order 0182 Angiogenesis research is also a cutting edge field in to reduce thrombus formation anticoagulation drugs are nec cancer research, and traditional therapies, such as radiation essary. The use of these drugs often results in undesirable therapy, may work in part by targeting the genomically stable systemic side effects and can be very problematic. Therefore endothelial cell compartment, rather than the genomically synthetic materials are poor choices for materials for Small unstable tumor cell compartment. New blood vessel forma diameter vascular grafts. By incorporating biological materi tion is a relatively fragile process, Subject to disruptive inter als into a synthetic vascular graft the host response can be ference at several levels. In short, the therapy is the selection modulated to help insure that the graft will not fail. The use of agent which is being used to kill a cell compartment. Tumor collagen as a material for a synthetic vascular graft is quite cells evolve resistance rapidly due to rapid generation time promising because it is biodegradable and has good mechani (days) and genomic instability (variation), whereas endothe cal properties. Since collagen is biodegradable, as the device lial cells are a good target because of a long generation time degrades tissue can grow into the device. This is advanta (months) and genomic stability (low variation). Angiogen geous because ideally as the collagen implant degrades the esis-based tumour therapy relies on natural and synthetic newly formed tissue will replace it, which results in a gradual angiogenesis inhibitors like angiostatin, endostatin and tum transfer of stress from the implanted device to the newly statin. These are proteins that mainly originate as specific formed tissue. fragments pre-existing structural proteins like collagen or 0186 If a collagen vascular implant material was seeded plasminogen. with endothelial cells so that they coat the lumen, the surface 0183 Recently, the 1st FDA-approved therapy targeted at would theoretically be more biocompatible. Recently, endot angiogenesis in cancer came on the market in the US. This is helial cells have been cultured onto the collagen small diam a monoclonal antibody directed against an isoform of VEGF, eter vascular grafts. Therefore by incorporating biodegrad and the therapy has been approved for use in colorectal cancer able peptides into the collagen vascular implant material, in combination with established chemotherapy. Therefore endothelial cells can be seeded onto the top of the material to there is a wide medical need for additional medicaments in create alumenal Surface that is comprised of endothelial cells the field of angiogenesis. to more closely mimic the natural biological environment. 0184 In addition, in terms of tissue engineering, medica Migration of endothelial cells on biomaterials is very impor ments that influence angiogenesis in vascular grafts are tant for the development of implantable devices. These cell needed. More than 450,000 vascular grafts were used in coro property controls the rates of reendothelization and angiogen nary bypass Surgeries annually. Other uses for vascular grafts esis that are important for the Success of the implant. include treatments for blood vessel aneurysms and fistulas, as 0187 Angiogenesis is a complex, multi-stage process by well as replacements for diseased arteries in other locations in which new blood vessels are formed from pre-existing vas the body. When possible, the best choice for a replacement culature. Two critical steps in this process are endothelial cell vessel is an autograft, where sections of the patient's healthy migration and assembly into new tubules. Over the last blood vessels (usually veins) are harvested and implanted in decade, diverse arrays of molecular regulators that participate the required location. Many patients, however, especially in the process of angiogenesis have been identified. The those with pre-existing vascular disease or patients that have receptor tyrosine kinases, for example, are one Such family of already had autograft procedures, do not have blood vessels angiogenesis regulators that play a prominent role in endot that are healthy enough to adequately serve as replacements. helial cell assembly and migration. US 2010/0204152 A1 Aug. 12, 2010

0188 The peptides of the present invention were tested syndrome, Adams-Oliver syndrome. Addison's disease, using the assays described in Examples 1-7, 9-17 for their Adenine phosphoribosyltransferase deficiency, Adenosine effect as active therapeutic agents in the prophylaxis and/or deaminase deficiency, Adenosylcobalamin deficiency, Aden treatment of heart and vascular diseases and disorders and of ovirus infection in immunocompromised patients, Adenylo diseases and disorders dependent on increased or decreased Succinase deficiency Adhesive arachnoiditis, Adie syndrome, angiogenesis. Adrenal adenoma, Adrenal hyperplasia, Adrenal incidenta (0189 Rare or Orphan Diseases loma, Adrenal insufficiency, Ad renocortical carcinoma, 0190. Another aspect of the present invention is directed to Adrenoleukodystrophy, Adrenomyeloneuropathy, the use of the peptide compound according to claim 1 or the Adrenomyodystrophy, Adult Onset Still's disease, Adult peptide combination according to claim 3 as a therapeutic T-cell leukaemia/lymphoma, Adult idiopathic neutropenia, agent for the prophylaxis and/or treatment of the following Adult neuronal ceroid lipofuscinosis (Kufs disease, CLN4), orphan diseases as well as for the prophylaxis and/or treat Adult spinal muscularatrophy, Afibrinogenemia, African tick ment of a heart and vascular disease, an autoimmune disease, typhus, African trypanosomiasis, Agammaglobulinemia, a fibrotic disease, an inflammatory disease, a neurodegenera Age-related macular degeneration, Ahn-Lerman-Sagie Syn tive disease, or an infectious disease, in patients suffering drome, Ahumada-Del Castillo syndrome, Aicardi syndrome, from one or more of the following Rare or Orphan Diseases: Aicardi-Goutieres syndrome, AIDS, Akaba hayasaka Syn (0191 ABCD syndrome, AAE, ABSD, ACPS III, ACRP drome, Akesson syndrome, Alagile syndrome, Alanine-gly syndrome, ACS, ACTH deficiency, isolated ACTH resis oxylate aminotransferase deficiency (hyperoxaluria type 1), tance, ADANE, ADCA, ADCME, ADEM, ADLTE, ADULT Albers-Schonberg disease, Albright hereditary osteodysto syndrome, AEC syndrome, AGM2, ARDS, AIDS wasting phy, Alcock syndrome, Aldolase A deficiency, Aldosterone syndrome, ALS, ALSG, AMME syndrome, ANOTHER syn synthase deficiency, Aldred syndrome, Alexander disease, drome, AOA1, AOS, APC, Autoimmune polyendocrinopa Algodystrophy, Alkaptonuria, Alkylglycerone phosphate thy-candidiasis-ectodermal dystrophy syndrome, APU synthase deficiency, Allan-Herndon-Dudley Syndrome, Doma, AR-CMT, ARC syndrome, ARCA, AREDYLD Allergic bronchopulmonary aspergillosis, Allgrove Syn syndrome, ASD, ASPED, ASPWSCR duplication, ATLD, drome, Alopecia, Alpers syndrome, Alpers-Huttenlocher ATR16, ATRUS syndrome, ATS-MR, AVED Aagenaes syn syndrome, Alpha-thalassemia, Alport syndrome, Alström drome, Aarskog like syndrome, Aarskog-Ose-Pande Syn syndrome. Alternating hemiplegia, Alveolar echinococcosis, drome, Aarskog-Scott syndrome, Aase syndrome, Aase Alves dos Santos castello syndrome, Alzheimer disease, Smith syndrome, Abdominal aortic aneurysm, Aberrant left Amaurosis-hypertrichosis, Ambras syndrome, Amegacaryo pulmonary artery, Abetalipoproteinemia, Ablepharon mac cytosis, Amelia, Aminoaciduria, Amoebiasis due to Entam rostomia syndrome, Abruzzo-Erickson syndrome, Acalvaria, oeba histolytica, Ampola syndrome, Amyloid cardiopathy, Acampomelic campomelic dysplasia, Acanthamoeba kerati Amyloid nephropathy, Amyloid polyneuropathy, Amyloido tis, Acanthocytic disorder, Acanthocytosis, Acanthosis nigri sis, Amylopectinosis, Amyoplasia congenita, Amyotrophic cans, Acatalasemia, Aceruloplasminemia, Achalasia, Achard lateral Sclerosis, Amyotrophy fat tissue anomaly, Anemia, Thiers syndrome, Ad Acheiropodia, Achondroplasia, Achro Anauxetic dysplasia, Ancylostomiasis, Andermann Syn matopsia, Acitretin embryofetopathy, Ackerman syndrome, drome, Andersen disease, Aneurysmal Subarachnoid haem Acoustic neurinoma, Acquired generalized lipodystrophy, orrhage, Angelman syndrome, Angio-osteohypertrophic Syn Acquired hypoprothrombinemia, Acquired ichthyosis, drome, Angiodysgenetic necrotizing myelopathy, Acquired idiopathic sideroblastic anaemia, Acquired Angioedema, Angiofollicular ganglionic hyperplasia, lipoatrophic diabates, Acquired prothrombin deficiency, Angiokeratoma, Angioma and vascular malformation, Angi Acrodermatitis enteropathica Zinc deficiency type, Acrodys omatosis systemic cystic Seip syndrome, Angioneurotic ostosis, Acrodysplasia, Acrofacial dysostosis, Acrokerato oedema, Angiostrongyliasis, Anguillulosis, Aniridia, derma, Acrokeratoelastoidosis, Acromelanosis, Acrome Anisakiasis, Ankylosing spondylarthritis, Ankylostomiasis, somelic dwarfism, Acromicric dysplasia, Acroosteolysis Annuloaortic ectasia, Anodontia, Anonychia, Anophthalmia dominant type, Acrorenal defect-ectodermal dysplasia diabe heart and pulmonary anomalies. Anorchidia, Anorexia ner tes, Acrorenal syndrome, Actinic porokeratosis disseminated Vosa, Anotia, Antenatal Epstein-Barr virus infection, Ante Superficial, Actinic porokeratosis, Acute Respiratory Distress riorhorn cell disease, Anti-phospholipid syndrome, Antinolo Syndrome, Acute basophilic leukaemia, Acute erythroblastic nieto borrego Syndrome, Antiplasmin deficiency, Antithrom leukaemia, Acute febrile neutrophilic dermatosis, Acute bin deficiency, Antley-Bixler syndrome, Anyane-Yeboa syn inflammatory demyelinating polyradiculoneuropathy (aidp). drome, Aorta coarctation, Aorta hypoplasia, Aorta-pulmo Acute interstitial pneumonia, Acute leukaemia of ambiguous nary artery fistula, Aortic aneurysm syndrome, due to lineage, Acute leukaemia of indeterminate lineage, Acute TGFbeta receptors anomalies, Aortic malformation, Aortic liver failure, Acute lymphoblastic leukaemia, Acute medul valve atresia, Aortic valve dysplasia, Aortic valve Stenosis, lary lesions, Acute megacaryoblastic leukaemia, Acute APECED syndrome, Apert syndrome, Aphasia, Apical bal monoblastic leukaemia, Acute motor and sensory axonal neu looning syndrome, Aplasia cutis, Aplastic anaemia, Apnea of ropathy (AMSAN), Acute motor axonal neuropathy infancy (AOI), Apnea of prematurity (AOP), Apo A-I defi (AMAN), Acute myeloblastic leukaemia, Acute myelodys ciency, Apollipoprotein AI amyloidosis, Apple peel Syn plasia with myelofibrosis, Acute myelofibrosis, Acute drome, Apraxia, Arbovirus fever, Arena syndrome, Areolar myeloid leukaemia in Down syndrome, Acute myelomono atrophy of the macula, Argyria, Argyrophilic grain disease, cytic leukaemia, Acute myelosclerosis, Acute non lympho Arhinia choanal atresia microphthalmia, Arkless-Graham blastic leukaemia, Acute panmyelosis with myelofibrosis, syndrome, Armfield syndrome, Arndt-Gottron disease, Acute peripheral arterial occlusion, Acute promyelocytic leu Arnold-Chiari malformation, Aromatase deficiency, kaemia, Acute tubulointerstitial nephritis and uveitis Syn Arrhinia, Arrhythmogenic right ventricular dysplasia, Arte drome, Adactylia unilateral, Adamantinoma, Adams nance rial calcification, Arterial duct anomalies, Arterial occlusive US 2010/0204152 A1 Aug. 12, 2010 16 disease, Arterial tortuosity, Arteriohepatic dysplasia, Arthritis Beaumont syndrome, Bonnemann-Meinecke-Reich syn juvenile, Arthrogryposis, Arthroophtalmopathy, Arthropathy, drome, Bonnet-Dechaume-Blanc syndrome, Book Syn Arts syndrome, Asbestosis, Ascher syndrome, Aseptic drome, Boomerang dysplasia, Booth haworth dilling abscesses syndrome, Aseptic osteitis, Asherman's syndrome, syndrome, Borjeson-Forssman-Lehmann syndrome, Bork Aspartylglucosaminidase deficiency, Asperger syndrome, syndrome, Bornholm eye disease, Bosley-Salih-Alorainy Aspergillosis, Asphyxiating thoracic dystrophy of the new syndrome, Bosma henkin christiansen syndrome, Bothnia born, Astley-Kendall dysplasia, Astrocytoma, Ataxia, Atelen retinal dystrophy, Boucher-Neuhauser syndrome, Bournev cephaly, Atelosteogenesis, Atherosclerosis, Atkin-Flaitz Syn ille syndrome, Boutonneuse fever, Bouwes Bavinck syn drome, Atransferrinemia, Atresia, Atrial cardiomyopathy, drome, Bowen Syndrome, Boyadjiev-Jabs syndrome, Boylan Atrial myxoma, Atrial septal defect, Atrichia, Atrioventricu dew syndrome, Brachman-de Lange syndrome, Brachydac lar canal complete-fallottetralogy, Atrophia aerata, Atropho tyly-arterial hypertension, Brachymesophalangy II and V. derma Vermiculata, Atypical Mole syndrome, Atypical Brachyolmia, Braddock carey syndrome, Bradyopsia, Brain Werner syndrome, Aughton Sloan milad syndrome, Aughton inflammatory disease, Brain injury, Brain Sclerosis, Brauer Hufnagle syndrome, Ausems wittebol post hennekam Syn syndrome, Braun bayer syndrome, Braun-Tinschert, Breast drome, Autism, Autoimmune haemolytic anemia, Autoim cancer, Brill-Zinsser disease, Brittle bone disease, Brody mune lymphoproliferative syndrome, Autoimmune myopathy, Bronchial carcinoid tumour, Bronchiectasis, pancreatitits, Axenfeld-Rieger syndrome, Ayazi syndrome, Bronchiolitis obliterans organizing pneumonia, Bronchiolitis B-cell chronic lymphocytic leukaemia, BAFME, BBB syn obliterans with obstructive pulmonary disease, Bronchogenic drome, X-linked, BCD, BEEC, BES, BIDS syndrome, BOD cyst, Bronchopulmonary dysplasia, Bronspiegel-Zelnick syndrome, BOFS, BOR syndrome, BOS syndrome, BPD, syndrome, Brooke-Spiegler syndrome, Brown-Vialetto-van BRESEK syndrome, BRESHECK syndrome, BRIC, BS, Laere syndrome, Bruce winship syndrome, Brucellosis, BSCL, BTHS, BTK-deficiency, Babesiosis, Bacterial toxic Bruck syndrome, Brugada syndrome, Brunner-Winter syn shock syndrome, Bahemuka brown syndrome, Baird syn drome, Brunzell syndrome, Bruyn Scheltens syndrome, drome, Balantidiasis, Ballard syndrome, Baller-Gerold syn Buckley syndrome, Budd-Chiari syndrome, Buerger's dis drome, Ballooning cardiomyopathy, Balo diseases, Bamforth ease, Bull-Nixon syndrome, Bulldog syndrome, Bulimia, syndrome, Bangstad syndrome, Banti Syndrome, Bannayan Bullous systemic lupus erythematosus, Buntinx lormans Riley-Ruvalcaba syndrome, Barachydactyly type A4, Barait martin syndrome, Burkitt lymphoma, Burn-McKeown syn ser burn fixen syndrome, Baraitser-Brett-Piesowicz syn drome, Burning Mouth syndrome, Buschke-Fischer-Brauer drome, Barakat syndrome, Barber-Say syndrome, Bardet syndrome, Buschke-Ollendorff syndrome, Buttiens-Fryns Biedl syndrome, Bare lymphocyte syndrome, Barnicoat syndrome, C syndrome, CACD, CACH syndrome, CADA baraitser syndrome, Barraquer-Simons syndrome, Barrett SIL, CAMAK syndrome, CAMFAK syndrome, CAMOS eosophagus, Barth syndrome, Bartonellosis, BartSocas-Papas syndrome, CANOMAD syndrome, CAP syndrome, CAPOS syndrome, Bartter syndrome, Basan syndrome, Bassen-Ko syndrome, CAPS (cryopyrin associated periodoc syndrome), rnZweig disease, Bassoe syndrome, Battaglia neri syndrome, CAR syndrome, CATCH 22, CATSHL syndrome, CAVC, Batten disease, Baughman syndrome, BazeX syndrome, CCFDN, CCGE syndrome, CDA type 1, CDG syndrome, Bazex-Dupre-Christol syndrome, Bazopoulou kyrkanidou CDGIIc, CDP, CDPD, CEDNIK syndrome, CFC syndrome, syndrome, Bd syndrome, Beals syndrome, Beals-Hecht syn CHAND syndrome, CREST syndrome, CRMO, CRV, CSD, drome, Bean syndrome, Beare Stevenson syndrome. Bech CSID, CSWSS syndrome, CVID, Cacchi-Ricci disease, Cafe terew syndrome, Beckwith-Wiedemann, Beemer-Ertbruggen au lait spots syndrome, Caffey disease, Cahmr syndrome, syndrome, Behcet disease, Behr syndrome, Behrens-Bau Calcinosis, Calderon gonzalez cantu syndrome, Calpainopa mann-Vogel syndrome, Bell's palsy, Bellini-Chiumello thy, Camera lituania cohen syndrome, Campomelia Cum Rimoldi syndrome, Benallegue Lacete syndrome, Beel, ming type, Camptodactyly, Camurati engelmann disease, Bencze syndrome, Bennion-Patterson syndrome, Benson's Canale-Smith syndrome, Canavan disease, Candidiasis, Can syndrome, Beradinelli-Seip syndrome, Berdon syndrome, talamessa baldini ambrosi syndrome, Canthus, Carbohydrate Berger disease, Berk tabatznik syndrome, Berlin breakage metabolism disorder, Cardiogenital syndrome, Cardiomy syndrome, Bernard-soulier syndrome, Berylliosis, Besnier opathy, Cardioskeletal myopathy, Carey fineman Ziter Syn Boeck-Schaumann disease, Bessel-Hagen disease, Best dis drome, Carnevale canun mendoza syndrome, Carnevale-Her ease, Beta thalassemia, Bethlem myopathy, Bickel-Fanconi nandez-del Castillo syndrome, Carnevale-Krajewska glycogenosis, Bickers-Adams syndrome, Bickerstaffs brain Fischetto syndrome, Carney complex, Carney-Stratakis stem encephalitis, Bicuspidaortic valve, Biemond syndrome, syndrome, Carnosinase deficiency, Carnosinemia, Caroli's Biermer disease, Bietti's crystalline dystrophy, Bile acid syn disease, Carpal Tunnel syndrome, Carpenter syndrome, Car thesis defect, Bile duct cancer, Biliary atresia, Biliary inflam penter-Waziri syndrome, Carrington's disease, Carrion dis matory disease, Bilineal acute leukaemia, Billard-Toutain ease, Carvajal syndrome, Casamassima-Morton-Nance Syn Maheut syndrome, Binder syndrome, Bindewald-Ulmer drome, Cassia Stocco dos Santos syndrome, Castleman Muller syndrome, Binswanger disease, Birt–Hogg–Dube disease, Castro gago pombo novo syndrome, Catalase defi syndrome, Bixler christian gorlin syndrome, Bjornstad Syn ciency, Cataract, Catel-Manzke syndrome, Cayler syndrome, drome, Blackfan-Diamond anaemia, Blaichman syndrome, Celiac disease, Celosomia, Cenani lenz Syndactylism, Cen Blake's pouch cyst, Blau syndrome, Blepharophimosis, Ble tral neurocytoma, Cephalopolysyndactyly, Ceramidase defi pharoptosis, Blepharospasm, Blethen wenick hawkins Syn ciency, Cerebellar hypoplasia, Cerebral arteriovenous shunt, drome, Bloch-Sulzberger syndrome, Bloom syndrome, Cerebral hemorrhage with amyloidosis, Cerebroretinal vas Blount disease, Blue Diaper syndrome, Bohring syndrome, culopathy, Cfc syndrome, Chagas disease, Chanarin disease, Bohring-Opitz syndrome, Boichis syndrome, Bone disease Chandler syndrome, Chang-Davidson-Carlson syndrome, with defective bone mineralisation, Bone disease with Chaotic atrial tachycardia, Char douglas dungan syndrome, increased bone density, Bone marrow failure, Bonneau Char syndrome, Charge. Syndrome, Charlevoix disease, US 2010/0204152 A1 Aug. 12, 2010

Charlie m syndrome, Chediak-Higashi like syndrome, Cronkhite canada syndrome, Cross syndrome, Crouzon dis Cheilitis glandularis, Chemke oliver mallek syndrome, ease, Crow-Fukase syndrome, Cryoglobulinaemia mixed, Chemodectoma, Cherry-red-spot myoclonus syndrome, Cryptococcosis, Cryptogenic organizing pneumonia, Cryp Cherubism, Chiari Frommel syndrome, Chitayat hajchahine tophthalmia, Cryptosporidiosis, Culler-Jones syndrome, syndrome, Chitayat moore del bigio syndrome, Chitayat Currarino triad, Curry-Hall syndrome, Curry-Jones syn Meunier-Hodgkinson syndrome, Chitty hall webb syndrome, drome, Cushing disease, Cutaneomeningospinal angiomato Chitty-Hall-Baraitser syndrome, Cholera, Cholestasis, Cho sis, Cutaneous lupus erythematosus, Cutaneous mastocy lesteryl ester storage disease, Choline acetyltransferase toma, Cutaneous mastocytosis, Cutaneous photosensitivity (Ch.AT) deficiency, Chondrocalcinosis, Chondrodysplasia, colitis, Cutaneous vasculitis, Cutaneuous myiasis, Cutis laxa, Chondrodystrophy, Chordoma, Choreoacanthocytosis, Cutler bass rom she syndrome, Cyclosporosis, CyStathioni Chorioretinal atrophy, Choristoma, Choroidal dystrophy, nuria, Cystic fibrosis, Cystic hamartoma of lung and kidney, Choroidal sclerosis, Choroideremia, Christ-Siemens-Tou Cystic lymphangioma, Cystic renal disease, Cystinosis, raine syndrome, Christian syndrome, Christian-Rosenberg Cystinuria, Cytochrome c oxydase deficiency, Cytomega syndrome, Christianson syndrome, Christianson-Fourie Syn lovirus (CMV) disease in patients with impaired cell medi drome, Christmas tree syndrome, Chromomycosis, Chronic ated immunity deemed at risk, Cytopenia, Czeizel brooser eosinophilic pneumonia, Chronic fatigue syndrome, Chronic syndrome, Czeizel losonci syndrome, Dercole syndrome, inflammatory demyelinating polyneuropathy, Chronic D-2-hydroxyglutaricaciduria, D-glycerate dehydrogenase myeloproliferative disease, Chronic neutrophilic leukaemia, deficiency (hyperoxaluria type 2), D-glycerate kinase defi Chronic pain requiring intraspinal analgesia, Chronic pneu ciency, D-glycericacidemia, DCMA syndrome, DCMD, monitis of infancy, Chronic osteomyelitis, Chronic spinal DEND syndrome, DI-CMT, DIDMOAD syndrome (Diabe muscular atrophy, Chudley rozdilsky Syndrome, Chudley tes Insipidus-Diabetes Mellitus-Optic Atrophy-Deafness), Lowry-Hoar syndrome, Churg-Strauss syndrome, Chylomi DIS, DK phocomelia syndrome, DKC, DOOR syndrome, cron retention disease, Ciliary dysentery, Ciliary dyskinesia DORY, DTDP1, DYT6, Da silva syndrome, Dacryocystitis bronchiectasis, Cilliers-Beighton syndrome, Cirrhosis osteopoikilosis, Daentl-Townsend-Siegel syndrome, Dahl associated cardiac dysfunction, Cirrhotic cardiomyopathy, berg-Borer-Newcomer syndrome, Daish hardman lamont Clarkson disease, Classical Hodgkin disease, Classical syndrome, Dancing Eye syndrome, Dandy walker malforma homocystinuria, Claude-Bernard-Homer syndrome, Clay tion, Daneman davy mancer syndrome, Danon disease, tonSmith-Donnai syndrome, Cleido rhizomelic syndrome, Darier disease, Darier-Gottron disease, Davenport donlan Cleidocranial dysostosis, Cleidocranial dysplasia, Clouston syndrome, David syndrome, Davies disease, Davis lafer syn syndrome, Coagulation disorder, Coarctation of aorta, Coats drome, De Barsy syndrome, De Hauwere-Leroy-Adriaens disease, Cobb syndrome, Cocaine poisoning, Cockayne Syn sens syndrome, De Santis-Cacchione syndrome, De Smet drome, Codas Syndrome, Coeliac disease, Coenzyme Q cyto Fabry-Fryns syndrome, De Vaal disease, De la Chapelle chrome c reductase deficiency, Coffin syndrome, Coffin dysplasia, De morsier syndrome, Deafness-Small bowel Lowry syndrome, Coffin-Siris Syndrome, Cogan syndrome, diverticulosis-neuropathy, Deal barratt dillon syndrome, Cogan-reese syndrome, Cohen hayden syndrome, Cohen Degos disease, Deerine-Sottas syndrome, Dekaban-Arima lockoodwyborney Syndrome, Cohen syndrome, Cole carpen syndrome, Delayed graft function after organ transplantation, ter syndrome, Colitis. Collagen anomaly, Collins pope Syn Delleman-Oorthuys syndrome, Dementia associated with a drome, Collins Sakati Syndrome, Coloboma, Colon cancer, metabolic disease, Dementia associated with a neurodegen Colonic atresia, Colorado tick encephalitis, Combined pitu erative disease, Dementia associated with an infectious dis itary hormone deficiencies, Complement component defi ease, Dementia associated with hepatic and renal failure, ciency, Congenital Lambert-Eaton-like syndrome, Congeni Demodicidosis, Dendritic cell sarcoma, Dendritic cell tumor, tal leptin deficiency, Congenital lobar emphysema, Dengue, Dennis cohen syndrome, Dennis fairhurst moore Conjunctival disease, Conjunctival vascular anomaly, Conn syndrome, Dense (delta) granule disease, Dent disease, Den syndrome, Connective tissue disease, Conradi-Hinermann tin dysplasia, Denys-Drash syndrome, Der Kaloustian Happle syndrome, Constrictive bronchiolitis, Cooks syn Jarudi-Khoury syndrome, Der kaloustian mcintosh silver drome, Cooley anaemia, Cooper-Jabs syndrome, Cormier syndrome, Dercum’s disease, Dermatofibrosarcoma protu rustin munnich syndrome, Corneal dystrophy, Cornelia de berans, Dermatologic allergic disease, Dermatostomatitis Lange syndrome, Corneodermatoosseous syndrome, Cor Stevens Johnson type. Desbuquois Syndrome, Desminopathy, neogoniodysgenesis, Coronaro-cardiac fistula, Coronary Desmoid disease, DesmoSterolosis, Devic's disease, arterial malformations, Coronary artery aneurysm, Coronary DeVriendt legius fryns syndrome, Devriendt vandenberghe sinus type ASD, Cortada koussef matsumoto syndrome, fryns syndrome, DiGeorge syndrome, Diabetes, Dialysis-re Costeff optic atrophy syndrome, Costeff syndrome, Costello lated arthropathy, Diaphanospondylodysostosis, Diaphrag syndrome, Cote katsantoni syndrome, Cousin-Walbraum matic agenesia, Diaphragmatic spinal muscularatrophy, Dif Cegarra syndrome, Cowchock syndrome, Cowchock-Wap fuse alveolar haemorrhage, Diffuse large B cell lymphoma, ner-Kurtz syndrome, Cowden syndrome, Coxoauricular syn Diffuse leiomyomatosis-Alport syndrome X-linked, Diffuse drome, Cramer-Niederdellmann syndrome, Crandall neonatal haemangiomatosis, Dihydropyrimidinuria, Dilated syndrome, Crane heise syndrome, Cranial malformation, cardiomyopathy with ataxia, DincSoy-Salih-Patel syndrome, Craniopharyngioma, Craniorachischisis, Craniostenosis, Dinno shearer weisskopf syndrome, Diomedibernardi pla Craniosynostosis, Craniotelencephalic dysplasia, Craniotu cidi syndrome, Dionisi-Vici-Sabetta-Gambarara syndrome, bular syndrome, Creatine deficiency, Creeping disease, Diphtheria, Diprosopia, Discoid lupus erythematosus, Dis Creutzfeldt-Jakob disease, Cri du chat syndrome, Crigler crete fibromuscular Subaortic Stenosis, Distichiasis-congeni Naijar syndrome, Crimean-Congo haemorragic fever tal heart defects-peripheral vascular anomalies, Distomato (CCHF), Crisponi syndrome, Criss-cross heart, Criswick sis, Dobrow syndrome, Donath-Landsteiner syndrome, Schepens syndrome, Crohn disease, Crome syndrome, Donnai-Barrow syndrome, Donohue syndrome, Doose Syn US 2010/0204152 A1 Aug. 12, 2010

drome, Dorfman-chanarin disease, Dowling-Degos disease, BlackSton-Oakley Syndrome, Fetal cytomegalovirus Syn Dowling-Degos-Kitamura disease, Down syndrome, Doyne drome, Fetal edema, Fetal left ventricular aneurysm, Fibrino honeycomb retinal dystrophy (DHRD), Drachtman weinblatt gen disorder, Fibrochondrogenesis, Fibrodysplasia ossificans sitarZ Syndrome, Drash syndrome, Dravet syndrome, Drum progressiva, Fibromatosis, Fibromuscular dysplasia of arter mond syndrome, Du Pan syndrome, Duane syndrome, ies, Fibromyalgia, Fibronectin glomerulopathy, Fibrosar Dubin-Johnson syndrome, Dubowitz syndrome, Duhring coma, Fibrosing mediastinitis, Fibrosis of extraocular brocq disease, Duker-Weiss-Siber syndrome, Dunnigan Syn muscles, Fiessinger-Leroy-Reiter's syndrome, Figuera syn drome, Dupont sellier chochillon syndrome, Dyggve-Mel drome, Filamin anomaly, Filariasis, Filippi Syndrome, Fine chior-Clausen disease, Dykes-Markes-Harper syndrome, Lubinsky syndrome, Finlay-Markes syndrome, Finucane Dyschondrosteosis, Dyschromatosis universalis, Dysferlin kurtz scott syndrome, Fitz Hugh Curtis syndrome, Fitzsim opathy, Dysfibrinogenemia, Dyskeratosis, Dysmorphic Syn mons-Guilbert syndrome, Fitzsimmons-McLachlan-Gilbert drome with connective tissue involvement, Dysosteosclero syndrome, Fitzsimmons-Walson-Mellor syndrome, Fixed sis, Dysostosis, Dysphagia lusoria, Dysplasia, Subaortic Stenosis, Flegel disease, Floating-Harbor Syn Dysprothrombinemia, Dyssegmental dysplasia glaucoma, drome, Florid cemento-Osseous dysplasia, Flynn aird syn Dysspondyloenchondromatosis, Dystoni-like syndrome with drome, Foix chavany marie syndrome, Foix-Alajouanine paroxysmal disease, Dystonia, EBD, EBJ, EBS, ECP syn syndrome, Follicular atrophoderma-basal cell carcinoma, drome, EDS III, EEC syndrome, EEM syndrome, EGE, ENT, Follicular dendritic cell sarcoma, Follicular dyskeratoma, ERA, ESS1, Eagle-Barret syndrome, Eales disease, Ebola Follicular ichthyosis, Follicular lymphoma, Fontaine-Farri virus disease, Echinocytic disorder, Ectodermal dysplasia, aux-Blanckaert syndrome. Forbes disease. Forney-Robin Ectromelia, Ectropion, Eczema-thrombocytopenia-immuno son-Pascoe syndrome, Forunculoid myiasis, Fountain Syn deficiency syndrome, Edinburgh malformation syndrome, drome, Fowler-Christmas-Chapple syndrome, Fox Fordyce Edward syndrome, Edwards-Patton-Dilly syndrome, Ehlers disease, Fra-X syndrome, Fragile X syndrome, Fragoso cid Danlos Syndrome, Ehrlichiosis, Eiken syndrome, Eisen garcia hernandeZ Syndrome, Franceschetti-Klein syndrome, menger syndrome, Elastosis perforans serpiginosa, Elejalde Francois dyscephalic syndrome, Francois Syndrome, Franek syndrome, Elliott ludman teebi syndrome, Elliptocytosis, bockerkahlen syndrome, Frank-Ter Haar syndrome, Franklin Ellis Van Creveld syndrome, Ellis yale winter syndrome, disease, Fraser like syndrome, Fraser syndrome, Frasier Syn Elsching syndrome, Emanuel Syndrome, Emery-Dreifuss drome, Freeman-Sheldon syndrome, Freiberg's disease, muscular dystrophy, Emery-Nelson syndrome, Empty Sella Freire maia pinheiro opitz syndrome, Frey's syndrome, Frias syndrome, Encephalitis, Encephalomyelitis, Encephalopa syndrome, Fried syndrome, Fried-Goldberg-Mundel syn thy, Enchondromatosis, Endometriosis, Endotheliitis, Eng drome, Friedman goodman syndrome, Friedreich ataxia, strom Syndrome, Engel congenital myasthenia, Engelhard Froelich's syndrome. Froster-Huch syndrome, Froster-Iske yatziv Syndrome, Enolase deficiency, Entericanendocrinosis, nius-Waterson syndrome, Fructosuria, Frydman-Cohen-Kar Enteropathy, Enterovirus antenatal infection, Entropion, mon syndrome, Fryns macrocephaly, Fryns-Aftimos Syn Envenomization, Eosinophilic endocarditis, Eosinophilic drome, Fryns-Hofkens-Fabry syndrome, Fuhrmann-Rieger pneumonia, Ependymoma, Epidermolysis bullosa, Epilepsy, de Sousa syndrome, Fukuda miyanomae nakata syndrome, Epiphyseal dysplasia, Episodic ataxia, Epispadias, Epithelial Fukuhara syndrome, Fuqua-Berkovitz syndrome, Furlong ovarian cancer, Epithelioma, Epstein-Barr virus infection, syndrome, Furukawatakagi nakao Syndrome, G syndrome, Erdheim disease, Erdheim-Chester disease, Eronen-Somer G6PD deficiency, GABA metabolism disease, GAMT defi Gustafsson syndrome, Erythema, Erythermalgia, Erythro ciency, GAPO syndrome, GIST, GM1 gangliosidosis, blastopenia, Erythrocytosis, Erythroderma, Erythrokerato GOSHS, GRACILE syndrome, GRF Tumour, GSD, GTN, derma, Erythromelalgia, Escher hirt syndrome, Escobar GVH, Gaisbock syndrome, Galactokinase deficiency, Galac syndrome, Esophageal adenocarcinoma, Esophageal atresia, tosemia, Galactosialidosis, Galloway syndrome, Galloway Essential cryoglobulinaemia, Essential iris atrophy, Essential Mowat Syndrome, Gamborg nielsen syndrome, Game-Fried osteolysis, Esthesioneuroblastoma, Estrogen receptor defi man-Paradice syndrome, Gamstorp episodic adynamy, ciency, Estrogen resistance syndrome, Evans syndrome, Ganglioglioma, Garcia torres guarner syndrome, Garcia-Lu Ewing sarcoma, Exner syndrome, Exostoses, EXSudative ret rie Syndrome, Gardner silengo wachtel syndrome, Gardner inopathy, Extracutaneous mastocytoma, Extrinsic allergic Morrison-Abbott syndrome, Garret tripp syndrome, Gastric alveolitis, Eye disease, F syndrome, FAP, FAS deficiency, cancer, Gastroschisis, Gaucher disease, Gaucher-like disease, FCS syndrome, FCU, FENIB, FEOM, FFDD type I, FG Geen Sandford davison syndrome, Gelineau disease, Gemig syndrome, FLOTCH syndrome, FOP, FOSMN syndrome, nani syndrome, Gemss syndrome, Genes syndrome, Geno FPS/AML syndrome, FRAXA syndrome, FRAXE syn chondromatosis, Gerbode defect, Gerhardt syndrome, Ger drome, FRAXF syndrome, FSH resistance, Fabry disease, man syndrome, Gershonibaruch-Leibo syndrome, Factor VII deficiency, Factor VIII deficiency, Factor X defi Gerstmann-Straussler-Scheinker syndrome, Ghosal Syn ciency, Factor XI deficiency, Factor XII deficiency, Factor drome, Gianotti Crosti syndrome, Giant cell arteritis, Giant XIII deficiency, Factors II,VII.IX and X, combined defi platelet syndrome, Gilbert syndrome, Gilles de la Tourette ciency, Fahr syndrome, Fallot complex. Familial LCAT defi syndrome, Gillespie syndrome, Gitelman syndrome, Glan ciency, Fanconi anaemia, Fanconi ichthyosis dysmorphism, Zmann thrombasthenia, Glass bone disease, Glass-Chapman Fanconi syndrome, Fanconi-Bickel disease, Fara-Chlu Hockley syndrome, Glaucoma, Glioblastoma, Glomerular packova syndrome, Farber lipogranulomatosis, Farmer's disease, Glomerulonephritis, Glomerulopathy with fibronec lung disease, Fatal infantile COX deficiency, Faulk-Epstein tin deposits (GFND), Gloomy syndrome, Glucagonoma, Jones syndrome, Favism, Fazio-Londe disease, Fechtner Syn Glucocorticoid resistance, Glycogen storage disease, Gms drome, Feigenbaum-Bergeron-Richardson syndrome, Fein syndrome, Goiter-deafness syndrome, Golabi-Rosen Syn gold syndrome, Felty syndrome, Fenton wilkinson toselano drome, Goldberg syndrome, Goldberg-Maxwell syndrome, syndrome, Ferlini-Ragno-Calzolari syndrome, Fernhoff Goldberg-Shprintzen megacolon syndrome, Goldblatt vil US 2010/0204152 A1 Aug. 12, 2010 19 joen Syndrome, Goldblatt wallis syndrome, Goldenhar Syn anaemia, Hemophilia, Hemorrhagiparous thrombocytic dys drome, Goldmann-Favre syndrome, Goldstein hutt syn trophy, Hennekam koss de geest syndrome, Hennekam Syn drome, Goldston syndrome, Gollop syndrome, Gollop drome, Hennekam-Beemer syndrome, Henoch-Schoenlein wolfgang complex, Goltz syndrome, Goltz-Gorlin syndrome, purpura, Hepatic cystic hamartoma, Hepatic fibrosis, Hepatic Gombo syndrome, Gonzales del angel syndrome, Goodman cancer, Hepatic venoocclusive disease, Hepatitis B re-infec syndrome, Goodpasture syndrome, Goossens-Devriendt Syn tion following liver transplantation, Hepatitis, Hepatoblas drome, Gordon syndrom, Gorham syndrome, Gorham-Stout toma, Hepatocellular adenoma, Hepatocellular carcinoma, disease, Gorlin syndrome, Gorlin-Chaudhry-Moss syn Hepatoerythropoeitic porphyria, Hepatoportal sclerosis, drome, Graft rejection after lung transplantation, Graft versus Hereditary coproporphyria, Hereditary endotheliopathy-ret host disease, Graham Boyle troxell syndrome, Graham-Cox inopathy-nephropathy-stroke, Hereditary lymphoedema type syndrome, Grand-Kaine-Fulling syndrome, Grange occlu I, Hereditary motor and sensory neuropathy, Hereditary vas sive arterial syndrome, Grant syndrome, Granulocytic sar cular retinopathie-Raynaud phenomenon-migraine, Herman coma, Granulomatous allergic angiitis, Granulomatous sky-Pudlak syndrome, Hernandez fragoso syndrome, Her inflammatory arthritis, dermatitis, and uveitis, Granuloma nandez-Aguirre Negrete syndrome, Herpes virus infection, tous mastitis, Graves' disease, Gray platelet syndrome, Herrmann opitz arthrogryposis syndrome, Hers disease, Greenberg dysplasia, Greig syndrome, Greither's disease, Hersh-Podruch-Weisskopf syndrome, Herva disease, Hetero Griscelli disease, Grix blankenshippeterson syndrome, Groll taxia, Heterozygous OSMED, Hillig syndrome, Hinman syn hirschowitz syndrome, Gronblad-Strandberg-Touraine syn drome, Hinson-Pepys disease, Hipo syndrome, Hirayama drome, Grosse syndrome, Grover's disease, Growth hormone disease, Hirschsprung disease, Hirsutism, His bundle tachy deficiency, Grubben de cock borghgraef syndrome, Gras cardia, Histidine metabolism disorder, Histidinuria renal beck-Imerslund disease, Guam disease, Guanidinoacetate tubular defect, Histiocytic and dendritic cell tumour. Histio methyltransferase deficiency, Guibaud-Vainsel syndrome, cytic sarcoma, Histiocytoid cardiomyopathy. Histiocytosis Guillain-Barré syndrome, Guizar-Vasquez-Luengas syn X, Histoplasmosis, Hittner hirschkreh syndrome, Hmc syn drome, GuizarVazquez-Sanchez-Manzano syndrome, Gunal drome, Hodgkin lymphoma, Hoepffner dreyer reimers Syn seber basaran syndrome, Gurrieri-Sammito-Bellussi syn drome, Hoffman's syndrome, Holmes benacerraf syndrome, drome, Gusher syndrome, Gynandroblastoma, Günther dis Holmes collins syndrome, Holmes-Gang syndrome, Holoac ease, HAD deficiency, HAE, HAIRAN syndrome, HANAC ardius amorphus, Holoprosencephaly, Holt-Oram syndrome, syndrome, HARD syndrome (Hydrocephalus-agyria-retinal Holzgreve Wagner rehder syndrome, Homocarnosinosis, dysplasia), HCDD, HCL, HDL metabolism disorder, HEM, Homocystinuria, Homogentisic acid oxydase deficiency, HEPHERNS syndrome, HHE syndrome, HHT, HHV-8, HID Hoon hall syndrome, Horner syndrome, Horton disease, syndrome, HIGM1, HIT, HMSN 5, HMSNP, HNPCC, Houlston ironton temple syndrome, House allergicalveolitis, HNSCC, HPA-1 deficiency, HPE, HSAN 1, HSD deficiency, Howard young syndrome. Howell-Evans syndrome, Hoyer HSV encephalitis, HSV keratitis, HUS, HVR, Haas-Robin aal-Hreidarsson syndrome, Humeroradial Synostosis, son syndrome, Haddad Syndrome, Haematologic cancers, Humeroradioulnar Synostosis, HumeroSpinal dysostosis, Haemochromatosis, Haemoglobin disorders, Haemolysis, Hunter carpenter mc donald Syndrome, Hunter jurenka Haemolytic anaemia, Haemolytic uremic syndrome, Haem thompson syndrome, Hunter syndrome, Hunter-Rudd-Hoff orrhagic fever, Haemorrhagiparous thrombocytic dystrophy, mann syndrome, Hunter-Thompson-Reed syndrome, Hun Hageman factor deficiency, Hagemoser weinstein bresnick tington disease, HurieZ Syndrome, Hurler syndrome, Hurler syndrome, Hailey-Hailey disease, Haim-Munk syndrome, Scheie syndrome, Hutchinson-Gilford syndrome, Hutteroth Hairy cell leukaemia, Hajdu-Cheney syndrome, Hal-Berg spranger syndrome, Hyaline membrane disease, Hyalu Rudolph syndrome, Halal syndrome, Halal-Setton-Wang ronidase deficiency, Hydatidosis, Hyde-Forster-Mccarthy syndrome, Hallermam streiff like syndrome, Hallermann Berry syndrome, Hygroma cysticum, Hyperaldosteronism, Streiff-Francois syndrome, Hallervorden-Spatz disease, Hyperargininemia, Hyperbilirubinemia, Hypercalciuria idio Hamanishi ueba tsuji Syndrome, Hamano tsukamoto Syn pathic, Hypercholesterolemia, Hyperchylomicronemia, drome, Hamman-Rich syndrome, Hanhart syndrome, Hand Hypercortisolism, Hyperexplexia, Hyperglycinemia, Hyper Foot Mouth syndrome, Hand-Shuller-Christian disease, imidodipeptiduria, Hyperinsulinism, Hyperkeratosis, Hyper Hanot syndrome, Hantavirus pulmonary syndrome, Hapnes lipidaemia, Hyperlipoproteinemia, Hyperlysinemia, Hyper boman skeie Syndrome, Happy puppet syndrome, Harboyan methioninemia, Hyperornithinemia, Hyperostosis, syndrome, Hardcastle syndrome, Harding ataxia, Harrod Hyperoxaluria, Hyperparathyroidism, Hyperphalangism syndrome, Harrod-Keele syndrome, Hartnup disorder, Harts dysmorphy bronchomalacia, Hyperphenylalaninemic field bixler demyer syndrome, Hashimoto struma, Hash embryopathy, Hyperpipecolatemia, Hypersensitivity pneu imoto-Pritzker syndrome, Haspeslagh-Fryns-Muelenaere monitis, Hypertelorism, Hyperthermia, Hyperthyroidism, syndrome, Hawkinsinuria, Hay wells syndrome, Heart block Hypertrichosis, Hypertrophic neuropathy, Hypertrophic or progressive, Heart-hand syndrome, Heavy chain deposition Verrucous lupus erythematosus, Hypertrophic Subaortic disease, Hec syndrome, Hecht Scott syndrome, Heckenlively Stenosis, Hypobetalipoproteinemia, Hypobetalipoproteine syndrome, Heide syndrome, Heimler syndrome, Heiner Syn mia, Hypochondroplasia, Hypocomplementaemic leucocy drome (cow’s milk hypersensitivity), Helmerhorst heaton toclasic vasculitis, Hypodontia, Hypofibrinogenemia, crossen syndrome, Hemangioma-thrombocytopenia Syn Hypokalemic alkalosis, Hypokeratosis, Hypomyelination, drome, Hemangiopericytoma, Hematopoietic hypoplasia, Hypoparathyroidism, Hypopituitarism, Hypoplastic left Hemeralopia, Hemi 3 syndrome, Hemiconvulsion-Hemiple heart syndrome, Hypoplastic right heart syndrome, Hypos gia-Epilepsy syndrome, Hemifacial hyperplasia Strabismus, padias, Hypothalamic hamartoblastoma syndrome, Hypothy Hemihypertrophy intestinal web corneal opacity, Hemimelia, roidism, Hypotrichosis, Hypoxanthine guanine phosphoribo Hemitruncus, Hemochromatosis, Hemoglobin C disease, syltransferase (HPRT) complete deficiency, I-cell disease, Hemoglobin E disease, Hemoglobin H disease, Hemolytic IBIDS syndrome, ICCA syndrome, ICE syndrome, ICF syn US 2010/0204152 A1 Aug. 12, 2010 20 drome, ICOS deficiency, IDI, IED, IFAP syndrome, IGDA, lagoyanni syndrome, Kaufman-Mckusick syndrome, IGF-1 deficiency, IGHD, IMAGe syndrome, INAD, INCL, Kawasaki disease, Kawashima syndrome, Kawashima-Tsuji IOMID syndrome, IOSCA, IPEX, IPSID, IRAK4 deficiency, syndrome, Kearns-Sayre syndrome, Kelley-Seegmiller Syn ISOD. ITP, IVC stenosis, Ichthyiosis, Idaho syndrome, Idio drome, Kelly-Kirson-Wyatt syndrome, Kennedy disease, pathic dystonia DYT1, Idiopathic granulomatous mastitis, Kennedy-Teebi Syndrome, Kennerknecht syndrome, Kenny Idiopathic hypereosinophilic syndrome, Idiopathic infantile syndrome, Kenny-Caffey syndrome, Kenya tick-bite fever, arterial calcification, Idiopathic infection caused by BCG or Keratinisation disorder associated with genetic eye disease, atypical mycobacteria, Idiopathic interstitial pneumonia, Keratitis, Keratoacanthoma, Keratoconus, Keratoderma, Idiopathic juvenile osteoporosis, Idiopathic myelofibrosis, Keratosis, Kerion celsi, Kersey Syndrome, Ketoacidosis, Idiopathic obliterative arteriopathy, Idiopathic orthostatic Ketoaciduria, Ketolysis disorder, Keutel syndrome, KGB hypotension, Idiopathic pulmonary fibrosis, Idiopathic syndrome, Khalifa-Graham Syndrome, Kienbock disease, thrombocytopenic purpura, leshima-Koeda-Inagaki Syn Kikuchi disease, Kikuchi-Fujimoto disease, Kimura disease, drome, Ilum syndrome, Ilyina amoashy grygory syndrome, King-Denborough syndrome, Kinsbourne syndrome, Imaizumi kuroki syndrome, Immune thrombocytopaenia, Klatskin tumour, Klein-Waardenburg syndrome, Kleine Immunodeficiency, Immunoproliferative Small intestinal dis Levin syndrome, Kleiner holmes syndrome, Klinefelter syn ease, Infant respiratory distress syndrome, Insulin-resistance drome, Klippel-Feil malformation, Klippel-Trenaunay Syn syndrome, Insulinoma, Interdigitating dendritic cell sarcoma, drome, Kluver-Bucy syndrome, Kniest dysplasia, Knobloch Intermediate DEND syndrome, Intermediate spinal muscular layer syndrome, Kocher-Debre-Semelaigne syndrome, atrophy, Internal carotid agenesis, Interstitial cystitis, Inter Kohler's disease, Kohlschutter-Tonz syndrome, Kok disease, Stitial granulomatous dermatitis with arthritis, Interstitial Komar syndrome, Konigsmark knox hussels syndrome, pneumonia, Interventricular septum aneurysm, Intestinal Kopysc barczyk krol syndrome, Kosenow syndrome, Kost atresia multiple, Intestinal epithelial dysplasia, Intestinal mann syndrome, Kosztoianyi syndrome, Koussef nichols hypomagnesemia with secondary hypocalcemia, Intestinal syndrome, Kousseff syndrome, Kowarski syndrome, lipodystrophy, Intestinal lipophagic granulomatosis, Intesti Kozlowski brown hardwick syndrome, Kozlowski massen nal lymphangiectasia, Intestinal pseudoobstruction, Intrac syndrome, Kozlowski ouvrier syndrome, Kozlowski tsuruta erebral haemorrhage, Intracranial aneurysms, Intracranial syndrome, Kozlowski-Krajewska syndrome, Krabbe disease, arterioVeinous malformation, Inverse Marcus-Gunn phenom Krasnow-Qazi syndrome, Krauss herman holmes syndrome, enon, Iridocorneal endothelial syndrome, Iridogoniodysgen Kudo tamura fuse syndrome, Kugelberg-Welander disease, esis, Irons-Bhan syndrome, Irritable bowel syndrome, Isaac's Kumar-Levick syndrome, Kunzeriehm syndrome, Kurczyn syndrome, Isaacs mertens syndrome, Ischaemic brain injury, ski-Casperson syndrome, Kuskokwim disease, Kuzniecky Ischemia/perfusion injury associated with Solid organ trans syndrome, Kynureninase deficiency, Kyphomelic dysplasia, plantation procedure, Ischio-vertebral dysplasia, Iso-Kikuchi Kyphosis brachyphalangy optic atrophy, Kissmaul-Maier syndrome, Isosporiasis, Isotretinoin syndrome, Isotretinoin disease, L1 syndrome, L-2-hydroxyglutaricaciduria, LADD like syndrome, Isovaleric acidemia, Itin syndrome, Ito syndrome. LBSL, LBWC syndrome, LCAD, LCAT defi hypomelanosis, Ivemark syndrome, JAE, JWS, Jackson-Barr ciency, LCCS, LCDD, LCH, LCHAD deficiency, LDD, syndrome, JacksOn-Weiss syndrome, Jacobs syndrome, LEOPARD syndrome, LGMD, LHCDD, LIG4 syndrome, Jacobsen syndrome, Jaffe campanacci syndrome, Jaffe-Lich LMS, LORD, LPI, Laband syndrome, Lachiewicz sibley syn tenstein disease, Jagell holmgrenhofer syndrome, Jalili Syn drome, Lactate dehydrogenase deficiency, Lactic acidosis, drome, Jancar syndrome, Japanese encephalitis, Jarcho Lactotrophadenoma, Ladda Zonanaramer syndrome, Lafora Levin Syndrome, Jaw-Winking syndrome, Jensen syndrome, disease, Laing distal myopathy, Lambdoid synostosis, Lam Jequier-Kozlowski syndrome, Jervell and Lange-Nielsen bert syndrome, Lambert-Eaton myasthenic syndrome, syndrome, Jeune syndrome, Job syndrome, Johanson-Bliz Lamellar ichthyosis, Laminopathy, Landau-Kleffner Syn Zard syndrome, Johnson syndrome, Johnson-McMillin Syn drome (LKS), Landing disease, LandouZy-Dejerine myopa drome, Johnson-Munson syndrome, Johnston-Aarons-Schel thy, Langer-Giedion syndrome, Langerhans cell granuloma ley Syndrome, Jones syndrome, Jorgenson lenz, syndrome, tosis, Langerhans cell histiocytosis, Langerhans cell Joubert syndrome, Joubert-Boltshauser syndrome, Juberg sarcoma, Laparoschisis, Laplane fontaine lagardere Syn hayward syndrome, Juberg-Marsidi syndrome, Judge misch drome, Laron syndrome, Larsen syndrome, Larsen-like Syn Wright syndrome, Jumping Frenchman of Maine, Jung Wolff drome, Laryngeal abductor paralysis, Laryngo onycho cuta back Stahl syndrome, Juvenile chronic myelomonocytic leu neous syndrome, Laryngo-tracheo-esophageal cleft kaemia, Juvenile gastrointestinal polyposis, Juvenile glau pulmonary hypoplasia, Lassa fever, LaSSueur-Graham-Little coma, Juvenile hemochromatosis, Juvenile hyaline fibroma syndrome, Late infantile neuronal ceroid lipofuscinosis, Late tosis, Juvenile idiopathic arthritis, Juvenile macular onset sepsis in premature infants, Lathosterolosis, Laubry degeneration, Juvenile myelomonocytic leukaemia, Juvenile peZZi Syndrome, Launois-Bensaude adenolipomatosis, Lau polyposis syndrome (JPS), Juvenile temporal arteritis, KBG rence-Moon syndrome, Laurin-Sandrow syndrome, syndrome. KBG-like syndrome, KID syndrome, Kabuki syn Lawrence syndrome, Lawrence-Seip syndrome, Laxova drome, Kaeser syndrome, Kahler's disease, Kaler garrity Opitz Syndrome, Le Merrer syndrome, Le marec bracq Stern syndrome, Kallin syndrome, Kallmann syndrome, picaud Syndrome, Leao-da Silva syndrome, Learman syn Kalyanaraman syndrome, Kanzaki disease, Kaplan-Plauchu drome, Leber plus disease, Leber congenital amaurosis, Fitch syndrome, Kaplowitz-Bodurtha syndrome, Kaposi's Leber miliary aneurysm, Left renal vein entrapment Syn sarcoma, Kaposiform hemangioendothelioma, Kapur-Tori drome, Left ventricular hypertrabeculation, Left ventricular ello syndrome, Karandikar-Maria-Kamble syndrome, Kar noncompaction, Legg-Calve-Perthes disease, Legionellosis, sch neugebauer syndrome, Kartagener syndrome, Kasabach Legionnaires disease, Leichtman-Wood-Rohn syndrome, Merritt syndrome, Kashani-Strom-Utley syndrome, Leifer lai buyse syndrome, Leigh disease, Leiner disease, Kasznica carlson coppedge syndrome, Katsantoni papadakou Leiomyomatosis of esophagus cataract hematuria, Leiomyo US 2010/0204152 A1 Aug. 12, 2010 matosis, Leiomyosarcoma, Leipala kaitila syndrome, Leish shek carr Syndrome, Macroglossia, Macrophage or histio maniasis, Leisti-Hollister-Rimoin syndrome, Lemierre Syn cytic tumour, Macrophagic activation syndrome, Macroph drome, Lenegre disease, Lennox-Gastaut syndrome, agic myofasciitis, Macrothrombocytopenia with leukocyte Leprechaunism, Leprosy, Leptospirosis, Leri pleonosteosis, inclusions, Macular amyloidosis, Macular dystrophy, Macu Leri-Weill syndrome, Lesch-Nyhan syndrome, Lethal arthro lar edema, Madelung's disease, Madras motor neuron dis gryposis with anterior horn cell disease (LAAHD), Lethal ease, Maffucci syndrome, Majeed syndrome, Majewxki chondrodysplasia moerman type, Lethal congenital contrac orturk syndrome, Major airway collapse, Meleda disease, ture syndrome, Lethal osteosclerotic bone dysplasia, Let Malakoplakia, Malakoplasia, Malaria, Malignant fibrous his terer-Siwe disease, Leucinosis, Leukaemia, Leukocyte adhe tiocytoma, Malignant germ cell tumor, Malignant hyperpyr sion deficiency (LAD), Leukodystrophy, exia, Malignant hyperthermia, Malignant mesenchymal Leukoencephalopathy, Leukonychia totalis, Leukotriene C4 tumor, Malignant paroxysmal ventricular tachycardia, Mal (LTC4) synthase deficiency, Levic Stefanovic nikolic Syn lory Weiss syndrome, Malouf syndrome, Maltase-glucoamy drome, Levine-Critchley syndrome, Levocardia, Levy-Hol lase deficiency, Maniac-depressive disorders, Manouvrier lister syndrome, Levy-Yeboa syndrome, Lewis-Pashayan syndrome, Mansonellosis, Mantle cell lymphoma, Maple syndrome, Lewis-Sumner syndrome, Lewy body dementia, syrup urine disease, Marashi gorlin syndrome, Marble brain Leydig cell hypoplasia, Lhermitte-Duclos disease, Li-Frau disease, Marburg disease, Marchiafava-Micheli disease, meni syndrome, Lichen, Lichstenstein syndrome, Liddle Syn Marcus-Gunn syndrome, Marden walker like syndrome, drome, Lindsay-Burn syndrome, Linear hamartoma Syn Marfan syndrome, Margarita island ectodermal dysplasia, drome, Linitis plastica, Lip-pit syndrome, Lipid storage Marin-Amat syndrome, Marinesco-Sjogren syndrome, disease, Lipodystrophy, Lipodystrophy-HIV, related, Marion mayers syndrome, Markel-Vikkula-Mulliken syn Lipoedemia, Lipoid proteinosis, Lipomatosis, Lipoprotein drome, Marles greenberg persaud syndrome, Maroteaux metabolism disease, Liposarcoma, Lisker-Garcia-Ramos cohen solalbonaventure syndrome, Maroteaux le merrer ben syndrome, Lissencephaly, Listeriosis, Little syndrome, Sahel Syndrome, Maroteaux Stanescu cousin Syndrome, Lobaratrophy of brain, Lobstein disease, Lobster-claw defor Maroteaux-Lamy syndrome, Maroteaux-Malamut Syn mity, Localized Castleman disease, Localized scleroderma, drome, Marsden nyhan Sakati Syndrome, Marshall syndrome, Locked-in syndrome, Loeffler's endocarditis, Loeys-Dietz Marshall-Smith syndrome, Martinez monasterio pinheiro syndrome, Loffredo cennamo cecio syndrome, Logic Syn syndrome, Martinez-Frias syndrome, Martsolf syndrome, drome, Loiasis, Long QT syndrome, Longman-Tolmie Syn Massa casaer ceulemans syndrome, Mast cell leukaemia, drome, Loose anagen syndrome, Lopes gorlin Syndrome, Mast cell sarcoma, Mastocytosis, Mastroiacovo de rosa satta Lopes marques de faria syndrome, Lopez-Hernandez Syn syndrome, Mathieu de broca bony Syndrome, Matsoukas drome, Lou-Gehrig disease, Louis-Bar syndrome, Lowe liarikos giannika syndrome, Matthew-Wood syndrome, kohn cohen syndrome, Lowe oculocerebrorenal syndrome, Mature B-cell tumour, Mature T-cell and NK-cell tumour, Lowe syndrome, Lower mesodermal defects, Lown-Ganong May-Hegglin thrombocytopenia, Mayer-Rokitansky-Küster Levine syndrome, Lowry syndrome, Lowry-MacLean Syn Hauser syndrome, Mazabraud syndrome, McArdle disease, drome, Lowry-Yong syndrome, Lubani-Al Saleh-Teebi syn McCabe's disease, McCune-Albright syndrome, McDon drome, Lubinsky syndrome, Lubs-Arena Syndrome, Lucey ough syndrome, McDowall syndrome, McGrath syndrome, driscoll Syndrome, Lucky gelehrter syndrome, Lujan-Fryns McKusick-Kaufman syndrome, McLeod syndrome, syndrome, Lunatomalacia, Lundberg syndrome, Lung agen McPherson-Hall syndrome, Mcalister crane syndrome, esis heart defect thumb anomalies, Lung cancer Small cell, Mccallum macadam johnston syndrome, Mcgillivray Syn Lung fibrosis, Lupus erythematosus, Luriekletsky syndrome, drome, Mclain-Dekaban syndrome, Mcpherson clemens Syn Luteinizing hormone releasing hormone deficiency with drome, Meacham winn culler syndrome. Meadows syn ataxia, Lutz-Richner-Landolt syndrome, Lyell syndrome, drome, Meckel like syndrome, Meckel syndrome, Meckel Lyme borreliosis, Lyme disease, Lymphangioleiomyomato Gruber syndrome, Meconium aspiration syndrome, Medeira sis, Lymphangioma, Lymphatic filariasis, Lymphatic malfor dennis donnai Syndrome, Mediastinal (thymic) large b-cell mation, Lymphedema, Lymphocyte apoptosis anomaly, lymphoma, Mediastinal diffuse large-cell lymphoma with Lymphocyte-depleted classical hodgkin lymphoma, Lym sclerosis, Mediastinal fibrosis, Medrano roldan syndrome, phocyte-rich classical hodgkin lymphoma, Lymphocytic Medullar disease, Medullary cystic kidney disease, Medullo colitis, Lymphoid interstitial pneumonia, Lymphomatoid blastoma, Megacalycosis, Megaduodenum and/or megacys granulomatosis, Lymphoproliferative disease associated with tis, Megaloblastic anaemia, Megarbane-Loiselet syndrome, primary immune disease, Lynch lee murday syndrome, Mehes syndrome, Mehta-Lewis-Patton syndrome, Meier Lynch syndrome, Lyngstadaas Syndrome, Lysosomal dis blumberg imahorn syndrome, Meier-Gorlin syndrome, ease, Lytico-bodig disease, M-CMTC, M/SCHAD, MAD, Meige disease, Meinecke pepper syndrome, Meinecke Syn MADSAM, MAE, MALT lymphoma, MASA syndrome, drome, Melanoma, Meleda disease, Melhem fahl syndrome, MCA, MCAD deficiency, MCOPS1, MDC1A, MEB Melioidosis, Melkersson rosenthal syndrome, Melnick (Muscle-Eye-Brain) syndrome, MEHMO syndrome, Needles syndrome, Melorheostosis, Membranoproliferative MELAS, MEN 1, MEN 2, MERRF syndrome, MGA type I, glomerulonephritis, Membranous glomerulopathy, Menetri MHBD deficiency, MIDD, MIRAS, MMEP syndrome, er's disease, Mengel konigsmark syndrome, Meniere's dis MMND, MNGIE syndrome, MOBA syndrome, MOCOD, ease, Meningioma, Meningitis, Menkes syndrome, Mental MODY syndrome, MORM syndrome, MPPH syndrome, retardation, Meretoja syndrome, Merkel cell carcinoma MPS, MRGH, MRKH syndrome, MRXS7, MSA, MTHFR (MCC), Merlob grunebaum reisner syndrome, Mesangial deficiency, MVA syndrome, MYH9, MacDuffie's syndrome, sclerosis, Mesodermic dysplasia, Mesothelioma, Mesulam Mac dermot winter syndrome, Maccario mena syndrome, syndrome, Metabolic intoxication disease, Metabolic liver Macdermot-Patton-Williams syndrome, Machado-Joseph disease, Metaphyseal dysplasia, Michels syndrome, Mickle disease, Macias flores garcia cruz rivera syndrome, Mackay son syndrome, Micro syndrome, Microcephaly, Microcoria, US 2010/0204152 A1 Aug. 12, 2010 22

Microcystic infiltrating lymphatic malformation, Microcytic NCMD, NF1, NFJ syndrome, NHL, NHPP. NISCH syn anaemia, Microphthalmia, Microscopic colitis Microtia, drome, NOMID syndrome, NPLCA, NSIP, NTD. Naegeli MicroVillous inclusion disease, Mid-aortic dysplastic Syn syndrome, Naegeli-Franceschetti-Jadassohn Syndrome, drome, Midas syndrome, Middle aortic syndrome, Midline Nager syndrome, Naguib syndrome, Nailanomaly, Nail dys heart, Mietens syndrome, Mievis verellen dumoulin syn plasia, Naito-Oyanagi disease, Nakagawa's angioblastoma, drome, Mikati naijar Sahli syndrome, Mikulicz disease, Mild Nakajo nishimura syndrome, Nakajo syndrome, Nakamura campomelic dysplasia, Miller syndrome, Miller-Dieker syn osame syndrome, Nance-Horan syndrome, Narcolepsy with drome, Miller-Fisher syndrome (MFS), Mills syndrome, Mil out cataplexy, Narcolepsy-Cataplexy, Nasodigitoacoustic roy disease, Minimal change nephrotic syndrome (MCNS), syndrome, Nasopharyngeal cancer, Nasu-Hakola disease, Minkowski-Chauffard disease, Mirhosseini-Holmes-Walton Nathalie syndrome, Navajo brainstem syndrome, Naxos dis syndrome, Mitral valve prolapse disease, Miura syndrome, ease, Necrotising hypophysitis, Necrotizing myelitis, Nema Mixed connective tissue disease, Mixed phenotype acute leu line myopathy, Neonatal Onset Multisystem Inflammatory kaemia, Mixed Sclerosing bone dystrophy, Miyoshi myopa Disease, Neonatal death immune deficiency, Neonatal hemo thy, MIs syndrome, Moderate and severe traumatic brain chromatosis, Neonatal neutropenia, Neonatal respiratory dis injury, Moebius syndrome, Moerman Vandenberghe fryns tress syndrome, Nephroblastoma, Nephrogenic fibrosing der syndrome, Moersch-Woltman syndrome, Moeschler clarren mopathy, Nephrogenic systemic fibrosis, Nephrolithiasis, syndrome, Mohr syndrome, Mohr-Trainebaerg syndrome, Nephronophthisis—hepatic fibrosis, Nephropathy, Nephro Mollica pavone antener syndrome, Moloney syndrome, sis, Nephrotic syndrome with diffuse mesangial sclerosis, Momo syndrome, Monilethrix, Mononen-Karnes-Senac syn Nephrotic syndrome, Nervous system tumour, Netherton dis drome, Monostotic fibrous dysplasia, Montefiore syndrome, ease, Neu-Laxova Syndrome, Neuhauser daly magnelli Syn Moore-Federman syndrome, Morava-Mehes syndrome, drome, Neuhauser eichner opitz syndrome, Neuhauser's Morgagni-Stewart-Morel syndrome, Morillo cucci passarge anomaly, Neural crest tumour, Neuroacanthocytosis, Neu syndrome, Morning glory syndrome, Morquio disease, Mor roaxonal dystrophy, Neuroblastoma, Neurocutaneous mel ris syndrome, Morse rawnsley Sargent syndrome, Morvan anosis, Neurodegeneration due to 3-hydroxyisobutyryl-CoA syndrome, Moschcowitz disease, Mounier-Kuhn syndrome, hydrolase deficiency, Neurodegeneration with brain iron Mousa-Al Din-Al Nassar syndrome. Movement disease, accumulation (NBIA), Neurodegenerative disease, Neuroec Mowat-Wilson syndrome, Moya-moya disease, Moynahan todermal syndrome, Neuroepithelioma, Neurofibromatosis, syndrome, Mpo deficiency, Msbd syndrome, Mseleni joint Neurolipomatosis, Neuromuscular junction disease, Neuro disease (MJD), Mucha Habermann Disease, Muckle-Wells myelitis optica, Neuromyotonia, Neuropathy, Neutral Lipid syndrome, Mucoepithelial dysplasia, Mucolipidosis, Muco Storage Disease, Neutropaenia, Nevo syndrome, Nevoid polysaccharidosis, Mucormycosis, Mucosal pemphigoid, hypermelanosis, Nezelof syndrome, Nicolaides baraitser Mucosulfatidosis, Muenke syndrome, Muir-Torre syndrome, syndrome, Niemann-Pick disease, Nievergelt syndrome, Mullerian aplasia, Multicentric Castleman disease (MCD), Niikawa-Kuroki syndrome, Nijmegen breakage syndrome, Multicentric giant lymph node hyperplasia, Multicentric Nivelon-Nivelon-Mabille syndrome, Noack syndrome, osteolysis, Multifocal acquired demyelinating sensory and Noble bass sherman syndrome, Nocardiosis, Nodular lym motor neuropathy, Multifocal pattern dystrophy simulating phocyte predominant Hodgkin lymphoma, Nodulosis-arthr fundus flavimaculatus, Multiglandular hyperplasia, Multi opathy-osteolysis syndrome. Noma, Non-24-Hour Sleep minicore disease (MmD), Multinodular goiter cystic kidney Wake syndrome. Non-DYT1 idiopathic torsion dystonia, polydactyly, Multiple carboxylase deficiency, Multiple con Non-Hodgkin malignant lymphoma, Non-alcoholic Steato tracture syndrome, Multiple cutaneous and uterine leiomyo hepatitis, Non-amyloid monoclonal immunoglobulin deposi mas, Multiple endocrine neoplasia, Multiple epiphyseal dys tion disease, Non-giant cell granulomatous temporal arteritis plasia, Multiple fibrofolliculoma, Multiple hamartoma with eosinophilia, Non-infectious uveitis affecting the poste syndrome, Multiple keratoacanthoma, Multiple pterygium rior segment of the eye, Nonaka myopathy, Nondysgermi syndrome, Multiple sclerosis, Multiple sulfatase deficiency, nomatous germ cell tumor, Noonan like contracture myopa Multiple system atrophy, Multiple ventricular septal defects, thy hyperpyrexia, Noonan like syndrome, Noonan syndrome, Mulvihill-Smith syndrome, MURCS association, Murray Normomorphic sialidosis, Norrie disease, Norum disease, Puretic-Drescher syndrome, Muscular channelopathy, Mus Nova syndrome, Novak syndrome, Nuclear cell envelopathy, cular dystrophy, Muscular fibrosis multifocal obstructed ves O donnell pappas syndrome, O'Doherty syndrome, sels, Mutchinick syndrome, Myalgia eosinophilia associated O'Sullivan-McLeod syndrome, OA-1, OCA, OCRL1, OFC with tryptophan, Myasthenia gravis, Myasthenic syndromes, syndrome, OFCD syndrome, OHSS, OLEDAID, ONMR Mycetoma, Mycoplasma encephalitis, Mycosis fungoides, syndrome, OPPG, ORW 2, OSLAM syndrome, OSMED, Myelinoclastic diffuse sclerosis, Myelinosis centralis diffusa, OTUDP syndrome, Obliterative portal venopathy, Occlusive Myelocerebellar disorder, Myelodysplastic or myeloprolif infantile arteriopathy, Occupational allergicalveolitis, Ochoa erative disease, Myelofibrosis with myeloid metaplasia, syndrome, Ochronosis, Oculo skeletal renal syndrome, Myeloid sarcoma, Myeloma, Myhre syndrome, Myiasis, Oculo-osteo-cutaneous syndrome, Oculoectodermal Syn Myoclonic dystonia, Myoclonic epilepsy, Myodysplasia, drome, Oculogastrointestinal muscular dystrophy, Oculomo Myofibrillar myopathy, Myoglobinuria, Myopathy and dia tor palsy, Oculomotor paralysis, Oculopharyngodistal betes mellitus, Myopathy, Myopia, Myositis ossificans pro myopathy, Odontologic disease, Odontomatosis, Oerter gressiva, Myotilinopathy, Myotonia congenita, Myotonic Friedman-Anderson syndrome, Oesophageal atresia, Oguchi disease, Myotubular myopathy, Myxofibrosarcoma, Myxoid disease, Ohaha syndrome, Ohdo madokoro Sonoda Syn liposarcoma, Myxoid malignant fibrous histiocytoma, drome, Ohtahara syndrome, Okamoto syndrome, Okihiro Myxoma with fibrous dysplasia, Möbius syndrome. N Syn syndrome, Oligocone syndrome, Oligomeganephronia, drome, NACG, NAGS deficiency, NAME syndrome, NAO Oliver mcfarlane syndrome, Oliver syndrome, Ollier disease, syndrome, NARP syndrome, NASH syndrome, NBS, NCL, Olmsted syndrome, Omenn Syndrome, Omodysplasia, Onat US 2010/0204152 A1 Aug. 12, 2010 syndrome. Onchocerciasis, Ondine syndrome, Ondine-Hir omyopathy, Peripheral T-cell lymphoma, Peripheral neur schsprung disease, Onychodystrophy, Oochs syndrome, opathy and optic atrophy, Peritoneal leiomyomatosis, Ophtalmic ichthyosis, Ophtalmoplegia, Opitz, BBB/G syn Peritumoral oedema derived from brain tumours, Periven drome, Opitz reynolds fitzgerald syndrome, Opitz-Caltabi tricular nodular heterotopia, Perlman syndrome, Pernicious ano syndrome, Opitz-Frias Syndrome, Oppenheim’s dysto anaemia, Perniola krajewska carnevale syndrome, Peroxiso nia, Opsismodysplasia, OpSoclonus-myoclonus syndrome, mal beta-oxidation disease, Perrault syndrome, Persistent Optic atrophy, Optic nerve hypoplasia, Optic neuropathy, Mullerian duct syndrome, Peters anomaly, Peters-plus syn Optic pathway glioma, Orbital leiomyoma, Ormond's dis drome, Petges-Cleat syndrome, Petit-Fryns syndrome, Petty ease, Ornithine aminotransferase deficiency, Orofaciodigital laxova wiedemann syndrome, Peutz-Jeghers syndrome, Pey syndrome, Oromandibular dystonia, Oroticaciduria, Oroya ronie syndrome, Pfeiffer mayer syndrome, Pfeiffer palm fever, Osebold-Remondini syndrome, Osgood-Schlatter dis teller syndrome, Pfeiffer rockelein syndrome, Pfeiffer syn ease, Osler-Vaquez disease, Osteoarthropathy, Osteoblas drome, Pfeiffer-Kapferer syndrome, Pfeiffer-Singer-Zschi toma, Osteochondritis, Osteochondromas, Osteochondrosis, esche syndrome, Pfeiffer-Weber-Christian syndrome, Phaco Osteocraniostenosis, Osteodysplasia, Osteoectasia, Osteo matosis, Phaeochromocytoma, Phagocyte function anomaly, genic sarcoma, Osteolysis, Osteomesopyknosis, Osteonecro Phaver syndrome, Phelan-McDermid syndrome, Phenotypic sis, Osteopaenia, Osteopathia striata—cranial sclerosis, diarrhoea, Phenylketonuria, Phocomelia, Phytosterolemia, Osteopetrosis, Osteopoikilosis, Osteoporosis, Osteosarcoma, Picardi-Lassueur-Little syndrome, Pick disease of brain, Pie Osteosclerosis, Ostravik lindemann solberg syndrome, Oto baldism, Pierre Robin sequence associated with branchial sclerosis, Ouvrier billson syndrome, Ovarian Sertoli-Leydig archs anomalies, Pierre Robin sequence associated with col cell tumor, Ovarian cancer, Ovarian germ cell malignant lagen diseases, Pigeon-breeder's lung disease, Pillay Syn tumor, Ovarioleukodystrophy, Oxalosis, PAF, PAGOD syn drome, Pilomatrixoma, Pilotto syndrome, Pinheiro freire drome, PAN, PANDAS, PAP. PAPA syndrome, PARC syn maia miranda syndrome, Pinsky-Di George-Harley Syn drome, PCA, PCARP, PCH with optic atrophy, PCT, PDALS, drome, Pitt-Hopkins syndrome, Pitt-Williams brachydactyly, PEHO syndrome, PEL, PELVIS syndrome, PFAPA syn Pitt-rogers-danks syndrome, Pituitary adenoma, Pituitary drome, PFIC, PHACE syndrome, PIBIDS syndrome, PJS, agenesis, Pituitary hormone deficiency, Pituitary lactotrophic PLOSL, PMD, PNDM, POADS, POEMS syndrome, POF, adenoma, Pityriasis rubra pilaris, Piussan-Lenaerts-Mathieu POMC deficiency, PPA, PPHS, PPM-X, PPoma, PSEK, PSP. syndrome, Plasma cell tumour, Platelet function disease, PTC-RCC, PTLAH, PTLD, Pachygyria, Pachyonychia, Pac Platyspondylic dysplasia, Plectin deficiency, Pleomorphic man dysplasia, Paediatric Autoimmune Disorders Associated liposarcoma, Pleuro-pulmonary blastoma, Pleuro-pulmonary with Streptococcus infections, Paediatric Autoimmune Neu endometriosis, Plott syndrome, Plum syndrome, Plummer ropsychiatric Disorders Associated with Streptococcus infec Vinson syndrome, Pneumoblastoma, Pneumocystosis, Pneu tions, Paediatric granulomatous arthritis, Paget disease, monia caused by Pseudomonas Aeruginosa, Poikilo-der Pagon Stephan syndrome, Pai syndrome, Pallister W syn matomyositis, Pollitt syndrome, Polyarteritis nodosa, drome, Pallister-Hall syndrome, Pallister-Killian syndrome, Polyarthritis, Polycystic kidney disease, Polycystic liver dis Palmer pagon syndrome, Palpebral disease, Panayiotopoulos ease, Polycystic ovarian disease, Polycythaemia, Polydac syndrome, Pancreatic carcinoma, Pancreatitis, Panner dis tyly, Polyepiphyseal dysplasia, Polymicrogyria, Polymor ease, Panniculitis, Panostotic fibrous dysplasia, Papillo-renal phic catecholergic ventricular tachycardia, Polymyositis, syndrome, Papillomatosis, recurrent respiratory, Papillon Polyostotic fibrous dysplasia, Polyposis, Polysyndactyly— Leage-Psaume syndrome, Papillon-Lefevre Syndrome, Papu cardiac malformation, Pompe disease, Popliteal web syn lar and Sclerodermoid lichen myxedematosus, Papular atri drome, Porokeratosis, Porphyria, Portal hypertension, Portal chia, Papular mucinosis of infancy, Paramyotonia, vein thrombosis, Post polio syndrome, Post transplantation Paraneoplastic pemphigus, Paraneoplastic retinopathy, graft dysfunction, Post-poliomyelitic syndrome, Post-trans Paraplegia, Parathyroid carcinoma, Parenchymatous liver plant lymphoproliferative disease, Post-traumatic syringo disease, Paris-Trousseau thrombocytopenia, Parkes-Weber myelia, Postanginal sepsis secondary to orophyngeal infec syndrome, Parkinson disease, Parkinsonism-dementia-ALS tion, Posterior cortical atrophy, Postpartum cardiomyopathy, complex, Paroxysmal cold haemoglobinuria, Paroxysmal Postviral Fatigue Syndrome, Potocki-Shaffer syndrome, Pot exertion-induced dyskinesia, Paroxysmal ventricular fibrilla tersequence, Powell chandra saal syndrome, Powell venencie tion, Parry-Romberg syndrome, Parsonage-Turner Syn gordon syndrome, Prader-Willi syndrome, Prata liberal gon drome, Partial deep dermal and full thickness burns, Parting calves syndrome, Preauricular pits renal disease, Precursor ton amyloidosis, Partington disease, Partington-Anderson B-cell acute lymphoblastic leukaemia, Precursor T-cell acute syndrome, Partington-Mulley Syndrome, Parvovirus antena lymphoblastic leukaemia, Preeyasombat-Varavithya syn tal infection, Pascuel castroViejo syndrome, Pashayan Syn drome, Pregnancy-related cholestasis, Premature aging, drome, Passwell-Goodman-Siprkowski syndrome, Patau Pressure-induced localized lipoatrophy, Prieto-Badia-Mulas syndrome, Patterned dystrophy of the retinal pigment epithe syndrome, Prieur-Griscelli syndrome, Primary biliary cirrho lium, Patterson pseudoleprechaunism syndrome, Patterson sis, Primary ciliary dyskinesia, Primary cutaneous CD30 Stevenson syndrome, Patterson-Lowry rhizomelic dysplasia, positive T-cell lymphoproliferative disorders, Primary effu Pauciarticular chronic arthritis, Pavone fiumara rizzo syn sion lymphoma, Primary effusion lymphoma associated with drome, Pearson syndrome, Peeling skin syndrome, Pelget the human immunodeficiency virus (HIV) infection, Primary Huer anomaly, Pelizaeus-Merzbacher brain sclerosis, Pella intestinal lymphangiectasia, Primary lateral Sclerosis, Pri gra, Pemphigus, Pena-Shokeir syndrome, Pendred mary lipodystrophy, Primary lymphoedema, Primary pulmo syndrome, Penta X syndrome, Pentosuria, Peptide metabo nary lymphoma, Primary Sclerosing cholangitis, Primerose lism disease, Peptidic growth factors deficiency, Perheentupa syndrome, Progeria, Progressive bulbar paralysis of child syndrome, Periarteritis nodosa, Pericardial defect diaphrag hood, Progressive cone dystrophy, Progressive diaphyseal matic hernia, Pericarditis, Perineurioma, Peripartum cardi dysplasia, Progressive massive osteolysis, Progressive neph US 2010/0204152 A1 Aug. 12, 2010 24 ropathy with hypertension, Progressive neuronal degenera syndrome, Robinow-Soraufsyndrome, Robinow-Unger syn tion of childhood with liver disease, Prolactinoma, Propping drome, Robinow-like syndrome, Roch-Leri mesosomatous Zerres syndrome, Prostate cancer, Proteus syndrome, Proud lipomatosis, Rocky Mountain spotted fever, Rodini richieri Levine-Carpenter syndrome, Prunebelly syndrome, Psoriatic costa syndrome, Roger disease, Roifman-Melamed Syn arthritis, PTEN Hamartoma syndrome, Pterygia, Pudendal drome, Rokitansky syndrome, Romano-Ward long QT syn neuralgia, Pudendal neuropathy, Pulmonar arterioVeinous drome, Rombo syndrome, Rommen mueller Sybert Syn aneurysm, Pulmonary Langerhans cell histiocytosis, Pulmo drome, Rosai-Dorfman disease, Rosenberg lohr syndrome, nary alveolar microlithiasis, Pulmonary alveolar proteinosis, Rosenberg Chutorian syndrome, Rothmund-Thomson Syn Pulmonary aortic Stenosis, Pulmonary arterial hypertension, drome, Rotor syndrome, Roy maroteaux kremp syndrome, Pulmonary arterio-veinous fistula, Pulmonary artery hypo Rozin-Hertz-Goodman syndrome, Rubinstein-Taybi syn plasia, Pulmonary atresia, Pulmonary blastoma, Pulmonary drome, Rudd-Klimek syndrome, Rudiger syndrome, Russell branch Stenosis, Pulmonary endometriosis, Pulmonary hae Silver syndrome, Russell weaver bull syndrome, Rutherfurd mosiderosis, Pulmonary insufficiency, Pulmonary lym syndrome, Ruvalcaba syndrome, Ruvalcaba-Myhre-Smith phangiectasia, Pulmonary lymphangiomatosis, Pulmonary syndrome, SADDAN, SANDO, SAPHO syndrome, SC pho nodular lymphoid hyperplasia, Pulmonary Supravalvular comelia, SCA, SCAN2, SCAR1, SCARF syndrome, SCASI, Stenosis, Pulmonary Surfactant protein anomalies, Pulmo SCD, SCID, SCLC, SE(M)D, SGBS, SGS, SHORT syn nary valve agenesis (PVA), Pulmonary venoocclusive dis drome, SIADH, SIBIDS syndrome, SJS, SLK, SMD, SMEI, ease, Pulp stones, Pulpal dysplasia, Puretic syndrome, Purtilo SMMCI, SOD, SOLAMEN syndrome, SPG, SPONAS syndrome, Pycnodysostosis, Pyknoachondrogenesis, Pykno TRIME dysplasia, SPS, SRP, SUNCT syndrome, Saal lepsy, Pyle disease, Pyoderma gangrenosum, Pyomyositis, Greenstein syndrome, Saccharopinuria, Sack-Barabas Syn Pyropoikilocytosis, Q fever, Qazi-Markouizos syndrome, drome, Saethre-Chotzen syndrome, Saito kuba tsuruta Quattrin mcpherson syndrome, RAEB-1, RAPADILINO syndrome, Sakati Syndrome, Sakati-Nyhan syndrome, syndrome, RB-ILD, RECQ2, RECQL3, RHS, Rabson-Men Sakati-Nyhan-Tisdale syndrome, Salcedo syndrome, Salla denhall syndrome, Radiation syndromes, Radio renal Syn disease, Salmonellosis, Salti salem syndrome, Sammartino drome, Raine syndrome, Rajab-Spranger syndrome, Ram decreccio syndrome, San Luis Valley syndrome, Sandhoff bam-Hasharon syndrome, Rambaud galian syndrome, disease, Sandifer syndrome, Sandrow syndrome, Sanfilippo Ramon syndrome, Ramos arroyo clark syndrome, Ramsay disease, Sanjad-Sakati Syndrome, Santavuori disease, San hunt syndrome, Randall disease, Rapp-Hodgkin ectodermal tos-Mateus-Leal syndrome, Sarcocystosis, Sarcoidosis, Sar dysplasia syndrome, Rapp-Hodgkin syndrome, Rasmussen cosinemia, Sarcosporidiosis, Satoyoshi syndrome, Say bar johnsen thomsen syndrome, Rasmussen syndrome, Rathburn ber hobbs syndrome, Say barber miller syndrome, Say field disease, Ray peterson Scott syndrome, Raynaud phenom coldwell syndrome, Say meyer syndrome, Scarring in glau enon, Reardon-Baraitser syndrome, Reardon-Hall-Slaney coma filtration Surgical procedures, Schaap taylor baraitser syndrome, Recurrent hepatitis C virus induced liver disease syndrome, Scheie syndrome, Scheuermann disease, Schil in liver transplant recipients, Red cell aplasia, Refetoff syn bach-Rott syndrome, Schilder disease, Schimke syndrome, drome, Reflex sympathetic dystrophy syndrome, Refsum dis Schimmelpenning syndrome, Schindler disease, Schinzel ease, Reginato-Schiapachasse syndrome, Reifenstein Syn syndrome, Schisis association, Schistosomiasis, Schmidt drome, Reinhardt pfeiffer syndrome, Reiter's syndrome, syndrome, Schmitt gillenwater kelly syndrome, Schnecken Renal adysplasia, Renal cell carcinoma, Renal dysplasia, becken dysplasia, Schnitzler syndrome, Schofer-Beetz-Bohl Renal glucosuria, Renal hypertension, Renal hypoplasia, syndrome, Scholte begeer Van essen syndrome, Schopf Renal nutcracker syndrome, Renal tubular acidosis, Renal Schulz-Passarge syndrome, Schwannomatosis, Schwartz tubular disorder, Renal-coloboma syndrome, Rendu-Osler Jampel syndrome, Scimitar syndrome, Scleroatrophic Syn Weber disease, Renier-Gabreels-Jasper syndrome, Renpen drome, Scleroderma, Scleromyxedema, Sclerosing ning syndrome, Resistance to activated protein C, Resistance mediastinitis, Sclerosteosis, Scott syndrome, Scott-Bryant to thyroid stimulating hormone, Respiratory bronchiolitis, Graham syndrome, Scott-Taor syndrome, Seaver cassidy Restless legs syndrome, Restrictive cardiomyopathy, Reticu syndrome, Sebastian syndrome, Seckel like syndrome, lar perineurioma, Retinal arteriolar tortuosity, Retinal degen Seckel syndrome, Sedlackova Syndrome, Seemanova lesny eration, Retinal dystrophy, Retinal hemorrhage, Retinoblas syndrome, Segawa syndrome, Seghers syndrome, Seitel toma, Retinohepatoendocrinologic syndrome, Retinopathy berger disease, Selig-Benacerraf-Greene syndrome, Sellars of prematurity, Retinoschisis with early hemeralopia, Retin Beighton syndrome, Sengers Syndrome, Sengers-Hamel-Ot oschisis, Retraction syndrome, Retroperitoneal fibrosis, Rett ten syndrome, Senior syndrome, Senior-Boichis syndrome, like syndrome, Rett syndrome, Revesz-Debuse syndrome, Senior-Loken syndrome, Sensenbrenner syndrome, Senter Reye's syndrome, Reynolds syndrome, Rh deficiency syn syndrome, Sepsis, Septic phlebitis of the internal jugular drome, Rhabdomyosarcoma, Rheumatic fever, Rhizomelic vein, Sequeiros sack syndrome, Servelle-Martorell syn dysplasia, Rhnull syndrome, Richards-Rundle syndrome, drome, Setleis syndrome, Severe closed traumatic brain Richardson's syndrome, Richieri Costa-Guion Almeida-Co injury, Severe combined immunodeficiency T-B-. Severe hen syndrome, Richieri costa da Silva syndrome, Richieri combined immunodeficiency with hypereosinophilia, Severe costa gorlin syndrome, Richieri-Costa-Colletto syndrome, combined immunodeficiency with leukopenia, Severe pneu RichieriCosta-Pereira syndrome, Richner-Hanhart syn mococcemia, Sezary's lymphoma, Shapiro syndrome, drome, Ricker syndrome, Rickettesiae disease, Riedel Thy Sharma kapoor ramji Syndrome, Sharp syndrome, Sheehan roiditis, Rieger syndrome, Right atrium familial dilatation, syndrome, Shigellosis, Shokeir syndrome, Shone syndrome, Right ventricle hypoplasia, Rigid spine syndrome, Riley-Day Short QT syndrome, Short bowel syndrome due to necrotiz syndrome, Riley-Smith syndrome, Rippberger aase Syn ing enterocolitis, Short bowel syndrome due to thrombosis, drome, Rippling muscle disease, Ritscher schinzel syndrome, Short bowel syndrome, Shprintzen omphalocele syndrome, Rivera-Perez-Salas syndrome, Roberts syndrome, Robinow Shprintzen-Goldberg syndrome, Shulman syndrome, US 2010/0204152 A1 Aug. 12, 2010

Shwachman-diamond syndrome, Shy-drager syndrome, sis), Systemic vasculitis, T cell immunodeficiency, T-cell leu Sialidosis, Sickle cell anaemia, Sideroblastic anaemia, kaemia, T-cell chronic lymphocytic leukaemia, TAC, TAR Sidransky-Feinstein-Goodman syndrome, Siegler brewer syndrome, TCP, TDO syndrome, TEMF, TGA, TINU syn carey Syndrome, Silengo lerone pelizZo syndrome, Silence drome, TNF receptor 1 associated periodic syndrome, TOS, syndrome, Simosa penchasZadeh bustos syndrome, Simpson TRAPS syndrome, TTP, TTR amyloid cardiopathy, TTR dysmorphia syndrome (SDYS), Simpson-Golabi-Behmel amyloid neuropathy, Tabatznik syndrome, Takatsuki Syn syndrome, Sinding-Larsen-Johansson disease, Singh drome, Takayasu arteritis, Takotsubo cardiomyopathy, Tang chhaparwal dhanda syndrome, Singh-Williams-McAlister hsi ryu syndrome, Tangier disease, Tardive dyskinesia, Tarsal syndrome. Single ventricular septal defect, Singleton-Merten Tunnel syndrome, Tarui disease, Tauopathy, Taussig-Bing dysplasia, Singleton-Merten syndrome, Sino-auricular heart syndrome, Tay Syndrome, Tay-Sachs disease, Taybi Syn block, Sinus node disease and myopia, Sipple syndrome, drome, Taybi-Linder syndrome, Teebi al Saleh hassoon syn Sirenomelia, Sitosterolemia, Situs inversus viscerum-cardi drome, Teebi kaurah syndrome, Teebi naguib alawadi Syn opathy, Sjögren syndrome, Sjögren-Larsson syndrome, Skel drome, Teebi shaltout syndrome, Telangiectasia, etal dysplasia, Skeletal muscle disease, Skin collagen dis Telecanthus, Telfer Sugar jaeger syndrome, Temtamy ease, Skin vascular disease, Sleep disorder, Sleeping Shalash syndrome, Ter Haar syndrome, Teratoma, Tetraame seekness, Sly disease, Small bowel adenocarcinoma, Small lia, Tetralogy of Fallot, Thakker donnai syndrome, Thalas bowel leiomyosarcoma, Small non-cleaved cell lymphoma, saemia syndrome, Thanatophoric dysplasia, Theodore's Smith martin dodd syndrome, Smith-Fineman-Myers syn syndrome. Thiele syndrome. Thiemann disease. Thies-Reis drome, Smith-Lemli-Opitz syndrome, Smith-Magenis syn syndrome, Thomas jewett raines syndrome, Thomas Syn drome, Sneddon syndrome, Sneddon-Wilkinson disease, drome, Thompson baraitser syndrome, Thomsen and Becker Snyder-Robinson syndrome, Soft tissue perineurioma, Soft disease, Thong douglas ferrante syndrome, Thoracic aortic tissue sarcomas, Sohval Soffer syndrome, Solitary plasmacy aneurysm and/or dissection, Thoracic outlet syndrome, Three toma, Solomon syndrome, Somatotroph adenoma, Sommer M disease. Thromboangiitis obliterans, Thrombocytopaenia, hines syndrome, Sommer rathbun battles syndrome, Som Thrombocytopenic purpura autoimmune, Thrombocytopenic mer-Young-Wee-Frye syndrome, Sondheimer syndrome, purpura idiopathic, Thrombocytosis, Thromboembolic pull Sonoda syndrome, Sorsby syndrome, Sorsby's fundus dys monary hypertension, Thrombotic disease of haematologic trophy, Sotos syndrome, Spastic paraplegia, Spellacy gibbs origin, Thymic aplasia, Thymic carcinoma, Thyroid tumor, watts syndrome, Spherophakia-brachymorphia, Sphingolipi Tick-borne encephalitis, Tietze syndrome, Timothy syn dosis, Spina bifida, Spinal atrophy, Spirillosis, Splenic mar drome, Tollner horst manzke syndrome, Tolosa-Hunt syn ginal Zone lymphoma, Spondylarthropathy, Spondylo camp drome, Tomaculous neuropathy, Tome brune fardeau Syn todactyly syndrome, Spondylocostal dysostosis, drome, Toni-Debré-Fanconi disease, Tonoki-Ohura-Niikawa Spondyloenchondrodysplasia, Spondyloepiphyseal dyspla syndrome, TORCH syndrome, Toriello syndrome, Toriello sia, Spongy degeneration of central nervous system, Spongy Carey syndrome, Toriello-Higgins-Miller syndrome, Tori myocardium, Spontaneous pneumothorax familial type, ello-Lacassie-Droste syndrome, Torres ayber syndrome, Sporotrichosis, Squamous cell carcinoma of head and neck, Tourette Syndrome, Townes-Brocks syndrome, Toxocariasis, St Louis encephalitis, Stalker chitayat Syndrome, Stampe Toxoplasma embryopathy, Toxoplasmosis, Tracheopathia Sorensen syndrome, Stapedo-Vestibular ankylosis, Staphylo osteoplastica, Tranebaerg-Sveigaard syndrome, Transmis coccal necrotizing pneumonia, Staphylococcal Scarlet fever, sible spongiform encephalopathies, Transposition of the Staphylococcal toxic shock syndrome, Stargardt disease, great arteries with pulmonary Stenosis, Transthyretinamyloid Stark-Kaeser syndrome, Startle disease, Steatocystoma, polyneuropathy, Treacher-Collins syndrome, Aspiration Steele-Richardson-Olszewski disease, Stein-Leventhal syn pneumotitis requiring intubation and mechanical ventilation, drome, Steinert myotonic dystrophy, Steinfeld syndrome, Cardiogenic shock, Treft-Sanborn-Carey syndrome, Trench Stern-Lubinsky-Durrie syndrome, Stevens-Johnson syn fever, Trevor disease, Triatrial heart, Trichinosis, Tricho ony drome, Stickler syndrome, Stiff person syndrome, Still dis chic dysplasia, Tricho-dento-Osseous syndrome, Tricho ease, Stimmler syndrome, Stoelinga de koomen davis Syn hepato-enteric syndrome, Trichorhinophalangeal, Trichor drome, Stoll alembik finck syndrome, Stoll geraudel chauvin rhexis nodosa syndrome, Trichothiodystrophy, Tricuspid syndrome, Stoll kieny doll syndrome, Stoll-Levy-Francfort atresia, Triopia, Triple A syndrome, Triple H (HHH) syn syndrome, Stomach cancer, Stormorken-Sjaastad-Langslet drome, Triplo-X syndrome, Trisomy, Tritanopia, Trochlear syndrome, Stratton garcia young syndrome, Stratton parker dysplasia, Tropical calcific chronic pancreatitis, Tropical syndrome, Streptobacillosis, Streptococcal toxic-shock Syn endomyocardial fibrosis, Truebburg bottani syndrome, Tsao drome, Stress cardiomyopathie, Strumpell-Lorrain disease, Ellingson syndrome, Tsukahara-Kajii syndrome, Tsukuhara Sturge-Weber syndrome, Stuve-Wiedemann dysplasia, Sub syndrome, Tsutsugamushi disease, Tsutsugamushi fever, cutaneous panniculitis-like T-cell lymphoma, Subpulmonary Tuberculosis, Tuberous sclerosis, Tubular duplication of the Stenosis, Sucking/swallowing disorder, Sudden infant death oesophagus, Tubular dysplasia, Tubular renal disease—car syndrome, Sugarman syndrome, Sujansky-Leonard Syn diomyopathy, Tubulointerstitial nephritis and uveitis Syn drome, Sulfocysteinuria, Summerskill-Walshe-Tygstrup syn drome, Tucker syndrome, Tuffli-Laxova syndrome, drome, Summitt syndrome, Supravalvar aortic Stenosis, Tularaemia, Tungiasis, Tungland-Bellman syndrome, Tunnel Susac syndrome, Sutton disease II, Sweet syndrome, Swyer Subaortic Stenosis, Turcot syndrome, Turner syndrome, syndrome, Symphalangism, Syncopal paroxysmal tachycar Turner-Kieser syndrome, Twin.twin transfusion syndrome, dia, Syncopal tachyarythmia, Syndromatic diarrhea, Syn Tylosis, ULD, UPDM, UPDP, USH, Uhl anomaly, Ulbright ovialosarcoma, Synovitis, Synspondylism, Syntelencephaly, hodes syndrome. Ulcerative colitis, Ulerythema ophryogen Syringocystadenoma papilliferum, Syringomyelia, Systemic esis, Ulick syndrome, Ullrich disease, Umbilical cord ulcer capillary leak syndrome, Systemic lupus erythematosus, Sys ation, Univentricular cardiopathy, Unverricht-Lundborg dis temic mastocytosis, Systemic Scleroderma (systemic Sclero ease, Upington disease, Upshaw-Schulman syndrome, US 2010/0204152 A1 Aug. 12, 2010 26

Urbach-Wiethe disease, Urban-Rogers-Meyer syndrome, drome. Wittwer syndrome, Wolcott-Rallison syndrome, Urban-Schosser-Spohn syndrome, Uremic pruritus, Urrets Wolf-Hirschhorn syndrome, Wolff Zimmermann syndrome, Zavalia syndrome, Usher syndrome. Usual interstitial pneu Wolff-Parkinson-White syndrome, Wolfram syndrome, Wol monia (UIP), Uveitis, VIPoma, VMCM, VODI syndrome, man disease, Woodhouse sakati syndrome, Woods black nor VSD. VWS, Vagneur triolle ripert syndrome, Van Allen-My bury syndrome, Woods leversha rogers syndrome, Woods hire syndrome, Van Benthem-Driessen-Hanveld syndrome, Crouchman-Huson syndrome, Worster drought syndrome, Van Bogaert disease, VanDerWoude syndrome, Vanbiervliet Worth syndrome, Wrinkly skin syndrome, Wyburn-Mason hendrickX Van ertbruggen syndrome, Van de berghe-De syndrome, XHIGM, XLAG syndrome, XMEA, XP, Xanthic queker syndrome, Van den Bosch Syndrome, Van den ende urolithiasis, Xanthinuria, Xanthogranulomatous hypophysi brunner syndrome, Van der Knapp syndrome, Van goethem tis, Xanthomatosis cerebrotendinous, Xerocytosis, Xero syndrome, Van maldergem wetzburger verloes syndrome, derma pigmentosum, Yellow fever, Yellow nail syndrome, Van regemorter piercquin Vamos syndrome, Varadi-Papp Syn Yersiniosis, Yorifuji-Okuno syndrome, Yoshimura-takeshita drome, Vascular leukoencephalopathy, Vasculitis, Vasquez syndrom, Young maders syndrome, Young syndrome, Young Hurst-Sotos syndrome, Vasterbotten dystrophy, Vein of Galen Hugues syndrome, Young-Simpson syndrome, Yunis-Varon aneurysm, Venencie powell winkelmann syndrome, Ventricu syndrome, ZASP-related myofibrillar myopathy, Zadik lar septal defect, Ventricular septal defect with aortic insuffi Barak-Levin Syndrome, Zellweger syndrome, Zellweger-like ciency, Verloes-Gillerot-Fryns syndrome, Verloes bourgui syndrome, Zimmer phocomelia, Zimmerman laband Syn gnon syndrome, Verloes david Syndrome, Verloes van drome, Zinsser-Cole-Engman syndrome, Zlotogora-Ogur maldergem marneffe Syndrome, Verloes-DepreZ Syndrome, syndrome, Zlotogura-MartineZ Syndrome, Zollinger-Ellison Verloove vanhorick brubakk syndrome, Verneuil disease, Vil syndrome, Zori Stalker williams syndrome, Zunich-Kaye joen winship syndrome, Viljoen-Kallis-Voges syndrome, Vil syndrome, Zygomycosis, 2.8 dihydroxy-adenineurolithiasis, joen-Smart syndrome, Viral hemorrhagic fever, Viral hepati 2-aminoadipic aciduria, 2-hydroxyglutaricaciduria, 2-meth tis, Viral vasculitis, Visceral neuropathy, Vitiligo, ylbutyric aciduria, 3 hydroxyisobutyric aciduria, 3-hydroxy Vitreoretinal degeneration, Vogt-Koyanagi-Harada disease, 3-methylglutaric aciduria, 3-methylcrotonylglycinuria, Vohwinkel syndrome, Volcke-Soekarman syndrome, Von 3-methylglutaconic aciduria, 3C syndrome, 3M syndrome, Gierke disease, Von Hippel-Lindau disease, Von Reckling 4-hydroxybutyricaciduria, Visceral leishmaniasis, Vernal hausen disease, Von Voss-Cherstvoy syndrome, Von Will keratoconjunctivitis, UV-A and visible light-induced photo ebrand disease, Von hippel anomaly, VSr syndrome, Vuopala sensitivity disorders (chronic actinic dermatitis, cutaneous disease, W syndrome, WAGR syndrome, WARBM1, WHIM porphyrias, actinic prurigo and solar urticaria), Uremic pru syndrome, WL syndrome, WT limb-blood syndrome, ritus, Tricyclic antidepressants poisoning, Traumatic spinal Waaler-Aarskog syndrome, Waardenburg syndrome, cord injury, Renal cell carcinoma, Superficial bladder cancer, Waardenburg-Shah syndrome, Wagner disease, Waisman Staphylococcus aureus bacteraemia, Spinal cord injury, syndrome, Waldenström macroglobulinemia, Waldmann dis Spina bifida, Soft tissue sarcoma, Small cell lung cancer, ease, Walker-Dyson syndrome, Walker-Warburg syndrome, Sickle cell disease, Severe myoclonic epilepsy in infancy, Wallis cremin beighton syndrome, Wallis Zieff goldblatt syn Severe combined immunodeficiency (SCID). Severe closed drome, Warburg Micro syndrome, Warburg thomsen syn traumatic brain injury, Retinopathy of prematurity, Retinitis drome, Warburton-Anyane-Yeboa syndrome, Warman-Mul pigmentosa, Respiratory distress syndrome in premature neo liken-Hayward syndrome, Water-West syndrome, nates of less than 32 weeks of gestational age, Recurrent Waterhouse-Friedrickson syndrome, Watson syndrome, hepatitis C virus induced liver disease in liver transplant Weaver like syndrome, Weaver syndrome, Weaver-Williams recipients, Radiation proctitis, Pseudomonas aeruginosa syndrome, Weber-Christian disease (WCD), Weber-Christian lung infection in cystic fibrosis, Progressive myoclonic epi panniculitis, Webster deming syndrome, Wegener granulo lepsies, Primary malignant bone tumors, Primary apnoea of matosis, Weil syndrome, Weill-Marchesani syndrome, Weis premature newborns, Post-transplant lymphoproliferative mann Netter Stuhl syndrome, Weissenbacher-Zweymuller disorders, Post-neonatal intracerebral haemorrhage, Post syndrome, Wellesley-Carman-French syndrome, Wells syn transplantation graft dysfunction, Polycythemia Vera, Peritu drome, Wells-syndrome, Werdnig-Hoffmann disease, moral oedema derived from brain tumors, Peripheral T-cell Wermer syndrome, Werner syndrome, Wernicke's encephal lymphoma (nodal, other extranodal and leukaemic/dissemi opathy, Wernicke-Korsakoff syndrome, West syndrome, nated), Ductus arteriosus in premature neonates of less than West-Nile encephalitis, Westerhof-Beemer-Cormane syn 34 weeks of gestational age, Partial deep dermal and full drome, Western equine encephalomyelitis, Westphall dis thickness burns, Paroxysmal nocturnal haemoglobinuria, ease. Whelan syndrome, Whipple disease, Whistling face Pancreatic cancer, Painful HIV-associated neuropathy, Ova syndrome, Whooping cough, Whyte-Murphy syndrome, rian cancer, Osteosarcoma, Orthostatic hypotension in Wieacker-Wolff syndrome, Wiedemann grosse dibbern syn patients with pure autonomic failure, Orthostatic hypotension drome, Wiedemann oldigs oppermann syndrome, Wiede in patients with multiple system atrophy, Ornithine-transcar mann-Beckwith syndrome, Wiedemann-Rautenstrauch syn bamylase deficiency, Oral mucositis in head and neck cancer drome, Wildervanck syndrome, Wilkes Stevenson syndrome, patients undergoing radiation therapy, Oesophageal cancer, Wilkie-Taylor-Scambler syndrome, Willebrand disease, Non-traumatic osteonecrosis, Non-ketotic hyperglyci Willi-Prader syndrome, Williams syndrome, Williams naemia, Non-infectious uveitis affecting the posterior seg Beuren syndrome, Wilms tumor, Wilson disease, Wilson ment of the eye, Non-24-hour sleep-wake disorders in blind Turner syndrome, Winchester disease, Winkelman bethge people with no light perception, Neuroblastoma, Neovascular pfeiffer syndrome, Winkelmann's cytophagic panniculitis, glaucoma, Nephritic syndrome, Myelodysplastic syndromes, Winship viljoen leary syndrome, Winter harding hyde syn Myasthenia gravis, Moderate and severe traumatic brain drome, Winter-Shortland-Temple syndrome, Wiskott-Ald injury, Metachromatic leukodystrophy, Medullary thyroid rich syndrome, Wissler-Fanconi syndrome. Witkop syn carcinoma, Mastocytosis, Mantle cell lymphoma, Malignant US 2010/0204152 A1 Aug. 12, 2010 27 melanoma, Malignant gastrointestinal stromal tumors, Mal Cava, Congenital Coronary Artery Arterio-Venous Fistula, absorption due to exocrine pancreatic enzyme insufficiency, Abnormal Origin of the Coronary Arteries, Aneurysm of the Low flow priapism, Lipoprotein lipase deficiency, Ligneous Sinus of Valsalva (Aortic Sinus Aneurysm), Endocardial conjunctivitis, Leber's hereditary optic neuropathy, Leber's Fibroelastosis, Idiopathic Hypertrophic Subaortic Stenosis congenital amaurosis, Late onset sepsis in premature infants (IHSS), Mitral Valve Prolapse—Barlow's Syndrome, Hypo of less than or equal to 32 weeks gestational age, Juvenile plastic Left Heart. myelomonocytic leukaemia, Japanese encephalitis, Intestinal 0.192 Pharmaceutical Compositions graft-Versus-host disease, Indolent non-Hodgkin's lym 0193 Still another aspect of the present invention relates phoma, Inborn errors in primary bile acid synthesis, Hyper to the use of the peptide according to claim 1 or the peptide phenylalaninemia, Hypereosinophilic syndrome, Glioma, combination according to claim 3 as an active ingredient, High-grade dysplasia in Barrett's oesophagus, Herpes sim together with at least one pharmaceutically acceptable car plex virus stromal keratitis, Hereditary factor XIII deficiency, rier, excipient and/or diluents for the manufacture of a phar Hepatocellular carcinoma, Hepatitis B re-infection following maceutical composition for the treatment and/or prophylaxis liver transplantation, Hepatic veno-occlusive disease, Gram of cancer, an autoimmune disease, a fibrotic disease, an negative bacterial lung infection in cystic fibrosis, Gastric inflammatory disease, a neurodegenerative disease, an infec cancer, Gamma sarcoglycanopathy, Follicular lymphoma, tious disease, a lung disease, a heart and vascular disease or a Familial adenomatous polyposis, Emphysema secondary to metabolic disease or any other disease disclosed herein. congenital alpha-1 antitrypsin deficiency, Duchenne muscu 0194 Such pharmaceutical compositions comprise the lar dystrophy, Diffuse large B cell lymphoma, Diffuse alveo peptide or peptide combination as an active ingredient, lar haemorrhage, Diarrhoea associated with intestinal together with at least one pharmaceutically acceptable car microSporidial infection, Cutaneous T-cell lymphoma, Cuta rier, excipient, binders, disintegrates, glidents, diluents, lubri neous forms of lupus erythematosus, Cushing's syndrome cants, coloring agents, Sweetening agents, flavoring agents, secondary to ectopic ACTH secretion, Corneal graft rejec preservatives or the like. The pharmaceutical compositions of tion, Congenital venous malformations, Congenital lym the present invention can be prepared in a conventional Solid phatic malformations, Congenital alpha-1 antitrypsin defi or liquid carrier or diluents and a conventional pharmaceuti ciency, Congenital adrenal hyperplasia, Chronic pain, cally-made adjuvant at Suitable dosage level in a known way. Cocaine poisoning, Chronic myeloid leukaemia, Chronic Preferably, the two peptides according to claim 3 are con lymphocytic leukaemia, Chronic iron overload requiring che tained in the combination in an amount from 20% by weight lation therapy, Chronic idiopathic myelofibrosis, Chronic of peptide 1 to 80% by weight of peptide 2 to 80% by weight eosinophilic leukaemia and the hypereosinophilic syndrome, of peptide 1 to 20% by weight of peptide 2. More preferably, Cholangiocarcinoma, Charcot-Marie-Tooth disease type 1A, the two peptides are contained in the combination in an Cardiogenic shock, Bronchopulmonary dysplasia in prema amount from 30% by weight of peptide 1 to 70% by weight of ture neonates of less than 30 weeks of gestational age, B-cell peptide 2 to 70% by weight of peptide 1 to 30% by weight of chronic lymphocytic leukemia, Autoimmune uveitis, Atypi peptide 2. Still more preferably the two peptides are con cal Haemolytic Uraemic Syndrome (aHUS) associated with tained in the combination in an amount from 40% by weight an inherited abnormality of the complement system, Aspira of peptide 1 to 60% by weight of peptide 2 to 60% by weight tion pneumonitis requiring intubation and mechanical venti of peptide 1 to 40% by weight of peptide 2. lation, Aneurysmal Subarachnoid haemorrhage, Anaplastic 0.195 Preferably the peptide or peptide combination is thyroid cancer, Anal fistula, Acute sensorineural hearing loss suitable for intravenous administration or suitable for oral (acute acoustic trauma, Sudden deafness and Surgery induced administration or suitable for administration by inhalation. acoustic trauma), Acute peripheral arterial occlusion, Acute 0196. Administration forms include, for example, pills, intermittent porphyria, Active phase of Peyronie's disease, tablets, film tablets, coated tablets, capsules, liposomal for Acanthamoebakeratitis, A-mannosidosis, 5q spinal muscular mulations, micro- and nano-formulations, powders and atrophy, Cavopulmonary Anastomosis, Atrial Septal Defects deposits. Furthermore, the present invention also includes (ASD), Partial Anomalous Pulmonary Venous Return, Per pharmaceutical preparations for parenteral application, sistent Common Atrio Ventricular Canal Endocardial Cush including dermal, intradermal, intragastral, intracutan, intra ion Defect. Ostium Primum, Single Atrium, Patent Ductus Vasal, intravenous, intramuscular, intraperitoneal, intranasal, Arteriosus (PDA), Total Anomalous Pulmonary Venous intravaginal, intrabuccal, percutan, rectal, Subcutaneous, Sub Return, Ventricular Septal Defects (VSD), Pulmonary Valve lingual, topical, or transdermal application, which prepara Stenosis, Pulmonary Artery Stenosis and Stenosis of Pulmo tions in addition to typical vehicles and/or diluents contain the nary Artery Branches, Pulmonary Atresia with Intact Ven peptide or peptide combination according to the present tricular Septum, Congenital Mitral Valve Disease, Aortic Val invention. Vular Stenosis and Congenital Aortic Valvular Regurgitation, 0197) The present invention also includes mammalian Supravalvular Aortic Stenosis, Transposition of the Great milk, artificial mammalian milk as well as mammalian milk Arteries, Double Outlet Right Ventricle, Corrected Transpo substitutes as a formulation for oral administration of the sition of the Great Arteries, Truncus Arteriosus, Aorta Pul peptide or peptides to newborns, toddlers, and infants, either monary Window, Tricuspid Atresia, Ebstein Anomaly, Mal as pharmaceutical preparations, and/or as dietary food formations of the Vena Cava, Coarctation of the Aorta, Atresia Supplements. of Aortic Valve. Anomalies of the Aortic Arch, Anomalous 0198 The peptide or peptide combination of the invention Origin of the Right Subclavian Artery with Coarctation of the can also be administered in form of its pharmaceutically Aorta, Idiopathic Dilatation of the Pulmonary Artery, Left active salts. Suitable pharmaceutically active salts comprise Pulmonary Artery Arising from Right Pulmonary Artery, acid addition salts and alkali or earthalkali salts. For instance, Dextrocardia—Situs Inversus Totalis, Association of Heart Sodium, potassium, lithium, magnesium or calcium salts can Malformations with Asplenia, Malformations of the Vena be obtained. US 2010/0204152 A1 Aug. 12, 2010 28

0199 The peptide or peptide combination of the invention active components and shaped in tablet form or capsules forms pharmaceutically acceptable salts with organic and containing such impregnated or encapsulated porous poly inorganic acids. Examples of Suitable acids for Such acid meric matrices. addition salt formation are hydrochloric acid, hydrobromic 0204 Aerosol preparations suitable for inhalation may acid, Sulfuric acid, phosphoric acid, acetic acid, citric acid, include solutions and Solids in powderform, which may be in oxalic acid, malonic acid, Salicylic acid, p-aminosalicylic combination with a pharmaceutically acceptable carrier Such acid, malic acid, fumaric acid, Succinic acid, ascorbic acid, as inert compressed gas, e.g. nitrogen. maleic acid, Sulfonic acid, phosphonic acid, perchloric acid, 0205 For preparing suppositories, a low melting wax such nitric acid, formic acid, propionic acid, gluconic acid, lactic as a mixture of fatty acid glycerides such as cocoa butter is acid, tartaric acid, hydroxymaleic acid, pyruvic acid, pheny first melted, and the active ingredient is dispersed homoge lacetic acid, benzoic acid, p-aminobenzoic acid, p-hydroxy neously therein by Stirring or similar mixing. The molten benzoic acid, methanesulfonic acid, ethanesulfonic acid, homogeneous mixture is then poured into convenient sized nitrous acid, hydroxyethanesulfonic acid, ethylenesulfonic molds, allowed to cool and thereby solidify. acid, p-toluenesulfonic acid, naphthylsulfonic acid, Sulfanilic 0206. Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form acid, campherSulfonic acid, china acid, mandelic acid, o-me preparations for either oral or parenteral administration. Such thylmandelic acid, hydrogen-benzenesulfonic acid, picric liquid forms include Solutions, Suspensions and emulsions. acid, adipic acid, D-o-tolyltartaric acid, tartronic acid, 0207. The peptides of the present invention may also be C-toluic acid, (o, m, p)-toluic acid, naphthylamine Sulfonic deliverable transdermally. The transdermal compositions acid, and other mineral or carboxylic acids well known to may take the form of creams, lotions, aerosols and/or emul those skilled in the art. The salts are prepared by contacting sions and can be included in a transdermal patch of the matrix the free base form with a sufficient amount of the desired acid or reservoir type as are conventional in the art for this purpose. to produce a salt in the conventional manner. 0208. The transdermal formulation of the peptide?s of the 0200. The pharmaceutical compositions according to the invention is understood to increase the bioavailability of said present invention will typically be administered together with peptide into the circulating blood. One problem in the admin suitable carrier materials selected with respect to the intended istration of peptides is the loss of bioactivity due to the for form of administration, i.e. for oral administration in the form mation of insolubles in aqueous environments or due to deg of tablets, capsules (either solid filled, semi-solid filled or radation. Therefore stabilization of peptides for maintaining liquid filled), powders for constitution. aerosol preparations their fluidity and maintaining their biological activity upon consistent with conventional pharmaceutical practices. Other administration to the patients in need thereof needs to be Suitable formulations are gels, elixirs, dispersible granules, achieved. syrups, Suspensions, creams, lotions, solutions, emulsions, 0209 Prior efforts to provide active agents for medication Suspensions, dispersions, and the like. Suitable dosage forms include incorporating the medication in a polymeric matrix for Sustained release include tablets having layers of varying whereby the active ingredient is released into the systemic disintegration rates or controlled release polymeric matrices circulation. Known Sustained-release delivery means of impregnated with the active components and shaped in tablet active agents are disclosed, for example, in U.S. Pat. No. form or capsules containing such impregnated or encapsu 4,235,988, U.S. Pat. No. 4,188,373, U.S. Pat. No. 4,100,271, U.S. Pat. No. 447,471, U.S. Pat. No. 4,474,752, U.S. Pat. No. lated porous polymeric matrices. The pharmaceutical com 4,474,753, or U.S. Pat. No. 4,478,822 relating to polymeric positions may be comprised of 5 to 95% by weight of the pharmaceutical vehicles for delivery of pharmaceutically peptide according to claim 1 or the peptide combination active chemical materials to mucous membranes. The phar according to claim 3. maceutical carriers are aqueous solutions of certain polyoxy 0201 As pharmaceutically acceptable carrier, excipient ethylene-polyoxypropylene condensates. These polymeric and/or diluents can be used lactose, starch, Sucrose, cellulose, pharmaceutical vehicles are described as providing for magnesium Stearate, dicalcium phosphate, calcium Sulfate, increased drug absorbtion by the mucous membrane and pro talc, mannitol, ethyl alcohol (liquid filled capsules). longed drug action by a factor of two or more. The Substitu 0202 Suitable binders include starch, gelatin, natural sug ents are block copolymers of polyoxypropylene and polyoxy ars, corn Sweeteners, natural and synthetic gums such as ethylene used for stabilization of drugs such as insulin. acacia, Sodium alginate, carboxymethyl-cellulose, polyethyl 0210 Aqueous solutions of polyoxyethylene-polyox ene glycol and waxes. Among the lubricants that may be ypropylene block copolymers (poloxamers) are useful as sta mentioned for use in these dosage forms, boric acid, sodium bilizers for peptides. Aside from serving as a stabilizer for the benzoate, sodium acetate, Sodium chloride, and the like. Dis peptides, poloxamers provide excellent vehicles for the deliv integrants include starch, methylcellulose, guar gum and the ery of the peptides, and they are physiologically acceptable. like. Sweetening and flavoring agents and preservatives may Poloxamers, also known by the trade name Pluronics (e.g. also be included where appropriate. Some of the terms noted Pluronic F127, Pluronic P85, Pluronic F68) have surfactant above, namely disintegrants, diluents, lubricants, binders and properties that make them useful in industrial applications. the like, are discussed in more detail below. Among other things, they can be used to increase the water 0203 Additionally, the compositions of the present inven solubility of hydrophobic, oily substances or otherwise tion may be formulated in sustained release form to provide increase the miscibility of two substances with different the rate controlled release of any one or more of the compo hydrophobicities. For this reason, these polymers are com nents or active ingredients to optimize the therapeutic effects. monly used in industrial applications, cosmetics, and phar Suitable dosage forms for sustained release include layered maceuticals. They have also been used as model systems for tablets containing layers of varying disintegration rates or drug delivery applications. In situ gelation of pharmaceutical controlled release polymeric matrices impregnated with the compositions based on poloxamer that are biologically trig US 2010/0204152 A1 Aug. 12, 2010 29 gered are known in the art (e.g. U.S. Pat. No. 5.256,396), particular importance for young infants because of the imma describing compositions containing poloxamer 407 and turity of the host defense and digestive systems early in life. water at specified concentrations. 0211. The term capsule refers to a special container or TABLE 1 enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing com Examples of the non-nutritional components of breast milk positions comprising the active ingredients. Hard shell cap Antimicrobial factors sules are typically made of blends of relatively high gel strength bone and pork skin gelatins. The capsule itself may Secretory IgA, IgM, IgG lactoferrin contain Small amounts of dyes, opaquing agents, plasticizers lysozyme and preservatives. complement C3 0212 Tablet means compressed or molded solid dosage leucocytes bifidus factor form containing the active ingredients with Suitable diluents. lipids and fatty acids The tablet can be prepared by compression of mixtures or antiviral mucins, GAGs granulations obtained by wet granulation, dry granulation or oligosaccharides by compaction well known to a person skilled in the art. Cytokines and anti 0213 Oral gels refers to the active ingredients dispersed or inflammatory factors solubilized in a hydrophilic semi-solid matrix. tumor necrosis factor 0214 Powders for constitution refer to powder blends interleukins interferons containing the active ingredients and Suitable diluents which prostaglandins can be suspended in water orjuices. One example for Such an antichymotrypsin oral administration form for newborns, toddlers and/or antitrypsin infants is a human breast milk substitute which is produced platelet-activating factor from milk powder and milk whey powder, optionally and Hormones partially substituted with lactose. feedback inhibitor of lactation (FIL) 0215 Human breast milk is a complex fluid, rich in nutri insulin ents and in non-nutritional bioactive components. It contains prolactin thyroid hormones all of the nutrients needed by the newborn baby. These corticosteroids include the metabolic components (fat, protein, and carbohy ACTH drates), water, and the raw materials for tissue growth and Oxytocin development, such as fatty acids, amino acids, minerals, Vita calcitonin parathyroid hormone mins, and trace elements. erythropoietin 0216. More than 98% of the fat in is in the form of trig Growth factors lycerides. Oleic acid and palmitic acid are the most abundant fatty acids in breastmilk triglycerides, with comparatively epidermal (EGF) high proportions of the essential fatty acids, and linolenic nerve (NGF) insulin-like (IGF) acid, followed by long-chain polyunsaturated fatty acids, transforming (TGF) Such as arachidonic acid and docosahexaenoic acid. These aurine long-chain fatty acids are constituents of brain and neural polyamines tissue and are needed in early life for mental and visual Digestive enzymes development. The lipid component of breast milk is the trans amylase port vehicle for fat-soluble micronutrients such as prostag bile acid-stimulating esterase landins and vitamins A, D, E, and K. bile acid-stimulating lipases 0217 Proteins account for approximately 75% of the ipoprotein lipase nitrogen-containing compounds in breast milk. Non-protein Transporters nitrogen Substances include urea, nucleotides, peptides, free actoferrin (Fe) amino acids, and DNA. The proteins of breast milk can be olate binder cobalamin binder divided into two categories: micellar caseins and aqueous gF binder whey proteins, present in the ratio of about 40:60. Casein hyroxine binder forms micelles of relatively small volume and produces a soft, corticosteroid binder flocculent curd in the infant’s stomach. The major whey pro teins are lactalbumin, lactoferrin, secretory IgA, and serum albumin, with a large number of other proteins and peptides 0220 Besides breast milk, infant formula is the only other present in Smaller amounts. infant milk which the medical community considers nutri 0218. The principal carbohydrate is lactose, a disaccha tionally acceptable for infants under the age of one year. ride produced in the mammary epithelial cell from glucose by Cow's milk is not recommended because of its high protein a reaction involving lactalbumin. and electrolyte (salt) content which may harm infant’s imma 0219. In addition to the nutritional components, breast ture kidneys. The nutrient content of infant formula should milk contains a wealth of bioactive components that have comprise: Protein, Fat, Linoleic acid, Vitamins: A, C, D, E, K, beneficial non-nutritional functions. These include a wide thiamin (B1), riboflavin (B2), B6, B12, Niacin, Folic acid, range of specific and non-specific antimicrobial factors; Pantothenic acid, Calcium, Metals: magnesium, iron, Zinc, cytokines and anti-inflammatory Substances; and hormones, manganese, copper; Phosphorus, Iodine, Sodium chloride, growth modulators, and digestive enzymes (Table 1), many of Potassium chloride. In addition, formulas not made with which have multiple activities. These components may be of cow’s milk must include biotin, choline, and inositol. US 2010/0204152 A1 Aug. 12, 2010 30

Hypoallergenic formulas reduce the likelihood of certain linked microcrystalline celluloses such as sodium medical complications in babies with specific health prob croScarmellose, alginates such as alginic acid and sodium lems. Baby formula can be synthesized from raw amino acids. alginate, clays such as bentonites, and effervescent mixtures. This kind of formula is sometimes referred to as elemental The amount of disintegrant in the composition can range from infant formula or as medical food because of its specialized about 1 to about 40% by weight of the composition, prefer nature. ably 2 to about 30% by weight of the composition, more 0221 Powder blends containing the active ingredients and preferably from about 3 to 20% by weight of the composition, Suitable diluents which can be suspended in water or juices and most preferably from about 5 to about 10% by weight. can be produced by spray drying. 0230 Binders characterize substances that bind or “glue' 0222 Spray drying has been found the most suitable pro powders together and make them cohesive by forming gran cess for removing the last part of the water, since spray drying ules, thus serving as the “adhesive' in the formulation. Bind can convert milk concentrate into a powder while still keeping ers add cohesive strength already available in the diluents or the valuable properties of the milk. The principle of all spray bulking agent. Suitable binders include Sugars such as dryers is to transform the concentrate into many Small drop Sucrose, starches derived from wheat, corn rice and potato; lets which are then exposed to a fast current of hot air. natural gums such as acacia, gelatin and tragacanth; deriva Because of the very large surface area of the droplets, the tives of seaweed such as alginic acid, Sodium alginate and water evaporates almost instantaneously and the droplets are ammonium calcium alginate; cellulosic materials such as transformed into powder particles. methylcellulose and sodium carboxymethylcellulose and 0223 Powdered milk is a powder made from dried milk hydroxypropyl-methylcellulose; polyvinylpyrrolidone; and solids. Powdered milk has a far longer shelf life than liquid inorganics such as magnesium aluminum silicate. The milk and does not need to be refrigerated due to its low amount of binder in the composition can range from about 1 moisture content. to 30% by weight of the composition, preferably from about 0224 Instant milk powder is produced by partially rehy 2 to about 20% by weight of the composition, more preferably drating the dried milk powder particles causing them to from about 3 to about 10% by weight, even more preferably become Sticky and agglomerate. The water is then removed from about 3 to about 6% by weight. by drying resulting in an increased amount of air incorporated 0231 Lubricant refers to a substance added to the dosage between the powder particles. form to enable the tablet, granules, etc. after it has been 0225 Milk powder manufacture is a process carried out on compressed, to release from the mold or die by reducing a large scale. It involves the gentle removal of water, while friction or wear. Suitable lubricants include metallic stearates retaining all the desirable natural properties of the milk like Such as magnesium Stearate, calcium Stearate or potassium colour, flavour, solubility, nutritional value. Stearate, Stearic acid; high melting point waxes; and water 0226 Milk powder process includes spray drying, fluid soluble lubricants such as Sodium chloride, Sodium benzoate, bed processing, extraction, evaporation and freeze drying. Sodium acetate, sodium oleate, polyethylene glycols and d'I- Other processes are freeze concentration, filteration, and leucine. Lubricants are usually added at the very last step homogenisation. before compression, since they must be present on the Sur 0227. The artificial mother milk formulations or mother faces of the granules and in between them and the parts of the milk substitutes of the present invention are preferably pre tablet press. The amount of lubricant in the composition can pared by adding to a mother milk formulation including com range from about 0.05 to about 15% by weight of the com mercially available mother milk formulations especially in position, preferably 0.2 to about 5% by weight of the com powder form the inventive peptide or peptide combination. position, more preferably from about 0.3 to about 3%, and The peptide or peptide combination is preferably added in an most preferably from about 0.3 to about 1.5% by weight of the amount of 3-100 ug peptide or peptide combination per 100 composition. ml (commercially available) mother milk formulation, more 0232 Glidents are materials that prevent caking and preferably in an amount of 5-70 ug/100 ml and most prefer improve the flow characteristics of granulations, so that flow ably in an amount of 10-40 ug/100 ml mother milk formula is Smooth and uniform. Suitable glidents include silicon diox tion. ide and talc. The amount of glident in the composition can 0228 Suitable diluents are substances that usually make range from about 0.01 to 10% by weight of the composition, up the major portion of the composition or dosage form. preferably 0.1% to about 7% by weight of the total composi Suitable diluents include Sugars such as lactose, Sucrose, tion, more preferably from about 0.2 to 5% by weight, and mannitol and sorbitol, starches derived from wheat, corn rice most preferably from about 0.5 to about 2% by weight. and potato, and celluloses such as microcrystalline cellulose. 0233 Coloring agents are excipients that provide colora The amount of diluents in the composition can range from tion to the composition or the dosage form. Such excipients about 5 to about 95% by weight of the total composition, can include food grade dyes and food grade dyes adsorbed preferably from about 25 to about 75%, more preferably from onto a Suitable adsorbent such as clay or aluminum oxide. The about 30 to about 60% by weight, and most preferably from amount of the coloring agent can vary from about 0.01 to 10% about 40 to 50% by weight. by weight of the composition, preferably from about 0.05 to 0229. The term disintegrants refers to materials added to 6% by weight, more preferably from about 0.1 to about 4% by the composition to help it break apart (disintegrate) and weight of the composition, and most preferably from about release the medicaments. Suitable disintegrants include 0.1 to about 1%. starches, “cold water soluble” modified starches such as 0234 Peptides of the invention can be used to form mul Sodium carboxymethyl starch, natural and synthetic gums tiparticulates, discrete particles, well known dosage forms, Such as locust bean, karaya, guar, tragacanth and agar, cellu whose totality represents the intended therapeutically useful lose derivatives such as methylcellulose and Sodium car dose of a drug. When taken orally, multiparticulates generally boxymethylcellulose, microcrystalline celluloses and cross disperse freely in the gastrointestinal tract, and maximize US 2010/0204152 A1 Aug. 12, 2010 absorption. A specific example is described in U.S. Pat. No. group of preferred buffers are nitrogen containing buffers 6,068,859, disclosing multiparticulates that provide con Such as imidazole, diethylenediamine, and piperazine. trolled release of azithromycin. Another advantage of the 0239. Also preferred are sulfonic acid buffers such as TES, multiparticulates is the improved stability of the drug. The HEPES, ACES, PIPES, (2-hydroxy-1,1-bis(hydroxym poloxamer component of the multiparticulate is very inert, ethyl)ethyl)amino-1-propanesulfonic acid (TAPS), 4-(2-hy thus minimizing degradation of the drug. droxyethyl)piperazine-1-propanesulfonic acid (EPPS), 0235 However, formulation problems result from the 4-Morpholinepropanesulfonic acid (MOPS) and N,N-bis(2- melt-congeal process often used to form multiparticulates. hydroxyethyl)-2-aminoethanesulfonic acid (BES). The multiparticulates are preferably formed into round beads 0240 Another group of preferred buffers are glycine buff or spheres. Some carriers, when melted and then solidified, do erS Such as glycine, glycyl-glycine, glycyl-glycyl-glycine, not form round beads but may solidify into rods, strings, or N,N-bis(2-hydroxyethyl)glycine and N-(2-hydroxy-11-bis other non-spherical shapes. The result is very irregularly (hydroxy-methyl)ethylglycine (Tricine). shaped multiparticulates that are difficult to process into dos 0241 Preferred are also amino acid buffers such as gly age forms. This problem is solved by e.g. WO 2007 104173 cine, alanine, Valine, leucine, isoleucine, serine, threonine, where the particles consist of a poloxamer, a resin, and/or a phenylalanine, tyrosine, tryptophane, lysine, arginine, histi tocopherol, creating together with the medicament (e.g. insu dine, aspartate, glutamate, asparagine, glutamine, cysteine, lin) micelles. Micelleformation is essential for the absorption methionine, proline, 4-hydroxyproline, N.N.N-trimethyll of many nutrients within the human body. Bile salts formed in ysine, 3-methylhistidine, 5-hydroxylysine, O-phosphoserine, the liver and secreted by the gallbladder allow micelles of Y-carboxyglutamate, e-N-acetyllysine, ()-N-methylarginine, fatty acids to form. This allows the absorption of complicated citruline, ornithine and derivatives thereof. lipids and lipid soluble vitamins within the micelle by the Small intestine. Micelles are approximately spherical in TABLE 2 shape. Preferably, peptides of the invention are formulated with apoloxamer and a resin to form micelles suitable for oral Also preferred are the following buffers: administration to patients in need of the medicament. effective pH range pKa 25°C. buffer 0236 Liquid form preparations include Solutions, Suspen 2.7-4.2 340 malate (pK1) sions and emulsions. As an example may be mentioned water 3.0-4.5 3.75 formate or water-propylene glycol Solutions for parenteral injections 3.0-6.2 4.76 citrate (pK2) or addition of Sweeteners and opacifiers for oral solutions, 3.2-5.2 4.21 Succinate (pK1) Suspensions and emulsions. Liquid form preparations may 36-56 4.76 acetate also include solutions for intranasal administration. 38-56 4.87 propionate 4.0-6.0 S.13 malate (pK2) 0237 Other preferred pharmaceutical compositions are 4.9-5.9 5.23 pyridine buffered solutions. The term buffer, buffer system, buffer 5.0-6.O 5.33 piperazine (pK1) 5.0-74 6.27 cacodylate solution and buffered solution, when used with reference to S.S.-6.5 5.64 Succinate (pK2) hydrogen-ion concentration or pH, refers to the ability of a S.S.-6.7 6.10 MES system, particularly an aqueous Solution, to resist a change of 5.5-7.2 6.40 citrate (pK3) pH on adding acid or alkali, or on dilution with a solvent. 5.5-7.2 6.24 maleate (pK2) SS-74 1.70, 6.04, 9.09 histidine Preferred buffer systems can be selected from the group con 5.8-7.2 6.46 bis-tris sisting of formate (pKa=3.75), lactate (pKa=3.86), benzoic 58-8.0 7.20 phosphate (pK2) acid (pKa=4.2) oxalate (pKa=4.29), fumarate (pKa=4.38), 6.O-12.O 9.SO ethanolamine aniline (pKa=4.63), acetate buffer (pKa=4.76), citrate buffer 6.O-7.2 6.59 ADA (pKa2=4.76, pKa2=6.4), glutamate buffer (pKa=4.3), phos 6.0-8.0 6.35 carbonate (pK1) 6.1-7.5 6.78 ACES phate buffer (pKa=7.20), succinate (pKa1=4.93: pKa2=5. 6.1-7.5 6.76 PIPES 62), pyridine (pKa=5.23), phthalate (pKa=5.41); histidine 6.2-7.6 6.87 MOPSO (pKa=6.04), MES (2-(N-morpholino)ethanesulphonic acid; 6.2-7.8 6.95 imidazole pKa=6.15); maleic acid (pKa=6.26); cacodylate (dimethy 6.3-9.5 6.80, 9.00 BIS-TRIS propane 6.4-7.8 7.09 BES larsinate, pKa=6.27), carbonic acid (pKa=6.35), ADA (N-(2- 6.5-7.9 7.14 MOPS acetamido)imino-diacetic acid (pKa=6.62); PIPES (4-pip 6.8-82 7.48 HEPES erazinebis-(ethanesulfonic acid; BIS-TRIS-propane(1,3-bis 6.8-82 740 TES tris(hydroxymethyl)methylamino-propane), pKa=6.80), 6.9-8.3 7.60 MOBS 7.0-8.2 7.52 DIPSO ethylendiamine (pKa=6.85), ACES 2-(2-amino-2-oxoethyl) 7.0-8.2 7.61 TAPSO aminoethanesulphonic acid; pKa=6.9), imidazole (pKa=6. 7.0-8.3 7.76 triethanolamine (TEA) 95), MOPS (3-(N-morphin)-propansulfonic acid: pKa=7. 7.0-9.0 0.91, 2.10, 6.70, 9.32 pyrophosphate 20), diethylmalonic acid (pKa=7.2), TES (2-tris 7.1-8.5 7.85 HEPPSO (hydroxymethyl)methylamino ethanesulphonic acid; 7.2-8.5 7.78 POPSO pKa=7.50) and HEPES (N-2-hydroxylethylpiperazin-N'-2- ethansulfonic acid; pKa=7.55) buffers or other buffers having 0242 Preferred are the buffers having an effective pH a pKa between 3.8 to 7.7. range of from 2.7 to 8.5, and more preferred of from 3.8 to 7.7. 0238 Preferred is the group of carboxylic acid buffers The effective pH range for each buffer can be defined as Such as acetate and carboxylic diacid buffers such as fuma pKa-1 to pKa--1, where Ka is the ionization constant for the rate, tartrate and phthalate and carboxylic triacid buffers such weak acid in the buffer and pKa=-log K. as citrate. Another group of preferred buffers is represented 0243 Most preferred are buffers suitable for pharmaceu by inorganic buffers such as Sulfate, borate, carbonate, tical use e.g. buffers Suitable for administration to a patient oxalate, calcium hydroxyde and phosphate buffers. Another Such as acetate, carbonate, citrate, fumarate, glutamate, lac US 2010/0204152 A1 Aug. 12, 2010 32 tate, phosphate, phthalate, and Succinate buffers. Particularly umole/ml. These are also the preferred ranges of the peptide preferred examples of commonly used pharmaceutical buff combination in the mother milk substitute or artificial mother ers are acetate buffer, citrate buffer, glutamate buffer and milk formulation or the pharmaceutical compositions dis phosphate buffer. Also most preferred is the group of car closed herein. boxylic acid buffers. The term "carboxylic acid buffers’ as Dietary Supplement used herein shall refer to carboxylic mono acid buffers and 0252) carboxylic diacid buffers as well as carboxylic triacid buffers. 0253 Still another aspect of the present invention relates Of course also combinations of buffers, especially of the to the use of the peptide according to claim 1 or the peptide buffers mentioned herein are useful for the present invention. combination according to claim 3 as a dietary Supplement. 0244. Some suitable pharmaceutical buffers are a citrate That dietary supplement is preferably for oral administration buffer (preferably at a final formulation concentration of from and especially but not limited to administration to newborns, about 20 to 200 mM, more preferably at a final concentration toddlers, and/or infants. A dietary Supplement is intended to of from about 30 to 120 mM) or an acetate buffer (preferably supplement the diet. The “dietary ingredients’ in these prod at a final formulation concentration of about 20 to 200 mM) or ucts may in addition include: Vitamins, minerals, herbs or a phosphate buffer (preferably at a final formulation concen other botanicals, amino acids, and Substances Such as tration of about 20 to 200 mM). enzymes, organ tissues, glandulars, and metabolites. Dietary 0245 Techniques for the formulation and administration Supplements may be manufactured in forms such as tablets, of the peptides of the present invention may be found in capsules, softgels, gelcaps, liquids, or powders. “Remington's Pharmaceutical Sciences’ Mack Publishing Co., Easton Pa. A suitable composition comprising at least 0254 Method of Treatment one peptide mentioned herein may be a solution of the peptide 0255 Another aspect of the present invention relates to a in a suitable liquid pharmaceutical carrier or any other for method of prophylaxis and/or treatment of cancer, an autoim mulation Such as tablets, pills, film tablets, coated tablets, mune disease, a fibrotic disease, an inflammatory disease, a dragees, capsules, powders and deposits, gels, syrups, slur neurodegenerative disease, an infectious disease, a lung dis ries, Suspensions, emulsions, and the like. ease, a heart and vascular disease or a metabolic disease or 0246 A particularly preferred pharmaceutical composi any other disease disclosed herein comprising administering tion is a lyophilised (freeze-dried) preparation (lyophilisate) to a patient in need thereof a pharmaceutical composition suitable for administration by inhalation or for intravenous comprising the peptide Ala-Val-Pro-Tyr-Pro-Gln-Arg in a administration. To prepare the preferred lyophilised prepara therapeutically effective amount effective to treat the afore tion the peptides of the invention are solubilised in a 4 to 5% mentioned disease. Another aspect of the present invention (w/v) mannitol solution and the solution is then lyophilised. relates to a method as described above wherein the peptide 1 The mannitol Solution can also be prepared in a Suitable is administered together with the peptide Tyr-Pro-Ile-Ser buffer solution as described above. Leu-OH (peptide 2) in order to treat cancer, the autoimmune 0247. Further examples of suitable cryo-flyoprotectants disease, the fibrotic disease, the inflammatory disease, the (otherwise referred to as bulking agents or stabilizers) include neurodegenerative disease, the infectious disease, the lung thiol-free albumin, immunoglobulins, polyalkyleneoxides disease, the heart and vascular disease or the metabolic dis (e.g. PEG, polypropylene glycols), trehalose, glucose, ease or any other disease disclosed herein Such as the orphan Sucrose, Sorbitol, dextran, maltose, raffinose, stachyose and disease. other saccharides (cf. for instance WO97/29782), while man 0256 Accordingly, the terms “prophylaxis' or “treat nitol is used preferably. These can be used in conventional ment includes the administration of the peptide or peptide amounts in conventional lyophilization techniques. Methods combination of the present invention to prevent, inhibit, or of lyophilisation are well known in the art of preparing phar arrest the symptoms of an infectious disease, an autoimmune maceutical formulations. disease, a fibrotic disease, an inflammatory disease, a neuro 0248 For administration by inhalation the particle diam degenerative disease, or a heart and vascular disease. In some eter of the lyophilised preparation is preferably between 2 to instances, treatment with the peptide or peptide combination 5 Lim, more preferably between 3 to 4 lum. The lyophilised of the present invention will be done in combination with preparation is particularly Suitable for administration using other protective compounds to prevent, inhibit, or arrest the an inhalator, for example the OPTINEB(R) or VENTA-NEB(R) symptoms of an infectious disease, an autoimmune disease, a inhalator (NEBU-TEC, Elsenfeld, Germany). The lyophi fibrotic disease, an inflammatory disease, a neurodegenera lised product can be rehydrated insterile distilled water or any tive disease, or a heart and vascular disease. other suitable liquid for inhalation administration. 0257 The term “active agent” or “therapeutic agent’ as 0249. Alternatively for intravenous administration the used herein refers to an agent that can prevent, inhibit, or lyophilised product can be rehydrated insterile distilled water arrest the symptoms and/or progression of an infectious, an or any other Suitable liquid for intravenous administration. autoimmune disease, a fibrotic disease, an inflammatory dis 0250. After rehydration for administration in sterile dis ease, a neurodegenerative disease, or a heart and vascular tilled water or another suitable liquid the lyophilised prepa disease or any other disease disclosed herein. ration should have the approximate physiological osmolality (0258. The term “therapeutic effect” as used herein, refers of the target tissue for the rehydrated peptide preparation i.e. to the effective provision of protection effects to prevent, blood for intravenous administration or lung tissue for inha inhibit, or arrest the symptoms and/or progression of an infec lation administration. Thus it is preferred that the rehydrated tious, an autoimmune disease, a fibrotic disease, an inflam formulation is substantially isotonic. matory disease, a neurodegenerative disease, or a heart and 0251. The preferred dosage concentration for either intra vascular disease. venous, oral, or inhalation administration is between 100 to (0259. The term “a therapeutically effective amount” as 2000 umole/ml, and more preferably is between 200 to 800 used herein means a Sufficient amount of the peptide or pep US 2010/0204152 A1 Aug. 12, 2010 tide combination of the invention to produce a therapeutic activity is between 25 to 100%. Even more preferably the effect, as defined above, in a subject or patient in need of increase of the activity or production of a biological pathway treatment. or molecule activity is between 50 to 100%. 0260. The terms “subject” or “patient” are used herein 0273. As used herein “mimic' is defined as an increase in mean any mammal, including but not limited to human the activity of a biological pathway dependent on the under beings, including a human patient or Subject to which the produced biological molecule of between 10 to 100%. More compositions of the invention can be administered. The term preferably the increase of the activity of the biological path mammals include human patients and non-human primates, way is between 25 to 100%. Even more preferably the as well as experimental animals such as rabbits, rats, and increase of the activity of the biological pathway is between mice, and other animals. 50 to 100%. 0261 The peptide or peptide combination of the present (0274 Peptides invention can be used for the prophylaxis and/or treatment of 0275. The following peptides were tested alone and in cancer, an autoimmune disease, a fibrotic disease, an inflam combination for their activity as a therapeutic agent for the matory disease, a neurodegenerative disease, an infectious prophylaxis and/or treatment of cancer, a heart and vascular disease, a lung disease, a heart and vascular disease or a disease, an infectious disease, an autoimmune disease, a metabolic disease or any other disease mentioned herein in fibrotic disease, an inflammatory disease, or a neurodegen combination administration with another therapeutic com erative disease: pound. As used herein the term “combination administration 0276 peptide 1 having the amino acid sequence: of a compound, therapeutic agent or known drug with the (0277 Ala-Val-Pro-Tyr-Pro-Gln-Arg, peptide or peptide combination of the present invention 0278 and the peptide 2 having the amino acid sequence: means administration of the drug and the peptide or peptide Tyr-Pro-Ile-Ser-Leu-OH (Gluten Exorphin C). combination at Such time that both the known drug and the (0279. The term “Gluten Exorphin C in brackets after the peptide or peptide combination will have a therapeutic effect. peptide sequence Tyr-Pro-Ile-Ser-Leu-OH is an abbreviation In some cases this therapeutic effect will be synergistic. Such or synonyme of said peptide No. 2. concomitant administration can involve concurrent (i.e. at the 0280 Concerning the peptide combination, both peptides same time), prior, or Subsequent administration of the drug are preferably contained in the inventive combination in a with respect to the administration of a peptide or peptide molar ratio of 1 mole peptide 1 to 5 mole peptide 2 to 5 mole combination of the present invention. A person of ordinary peptide 1 to 1 mole peptide 2, more preferred in a molar ratio skill in the art would have no difficulty determining the appro of 1 mole peptide 1 to 4 mole peptide 2 to 4 mole peptide 1 to priate timing, sequence and dosages of administration for 1 mole peptide 2, still more preferred in a molar ratio of 1 particular drugs and peptide or peptide combination of the mole peptide 1 to 3 mole peptide 2 to 3 mole peptide 1 to 1 present invention. mole peptide 2, still more preferred in a molar ratio of 1 mole 0262 Definition of Peptide Activity peptide 1 to 2 mole peptide 2 to 2 mole peptide 1 to 1 mole 0263. A peptide or peptide combination is deemed to have peptide 2, and most preferred in a molar ratio of 1 mole therapeutic activity if it demonstrated any one of the follow peptide 1 to 1.5 mole peptide 2 to 1.5 mole peptide 1 to 1 mole ing activities listed in a) to g). peptide 2. Preferred ratios of the peptides in % by weight are 0264 a) The peptide could inhibit the activity of an over disclosed above which can be used instead of the ratios men active biological pathway. tioned as molar rates. 0265 b) The peptide could inhibit the production of an 0281 Furthermore the present invention relates to the use over produced biological molecule. of the above-mentioned peptide or peptide combination as 0266 c) The peptide could inhibit the activity of an over pharmaceutically active agents in medicine, i.e. as medica produced biological molecule. ment. Advantage of the peptide and peptide combination is 0267 d) The peptide could increase the activity of an that the peptide and peptide combination are less toxic in under active biological pathway. comparison to the commonly used drugs for the certain indi 0268 e) The peptide could increase the production of an cations mentioned herein and that the peptide and peptide under produced biological molecule. combination have less side effects, can be used for a long term 0269 f) The peptide could mimic the activity of an under treatment of certain diseases and can be easily administered. produced biological molecule. Moreover the peptide and peptide combination are selective 0270 g) The peptide could prevent, inhibit, or arrest the for certain targets and under physiological conditions notoxic symptoms and/or progression of cancer, an infectious dis or noxious degradation products are formed. ease, an autoimmune disease, a fibrotic disease, an inflam 0282. As used herein, the term "peptide' refers to peptide matory disease, a neurodegenerative disease, or a heart and 1 which is and the term "peptide combination” refers to the vascular disease or any other disease disclosed herein. combination of peptide 1 and peptide 2. The terms “peptide' 0271. As used herein “inhibition' is defined as a reduction and "peptide combination' shall also refer to salts, depro of the activity or production of a biological pathway or mol tected for, acetylated form, deacetylated form, enantiomers, ecule activity of between 10 to 100%. More preferably the diastereomers, racemates, prodrugs and hydrates of the reduction of the activity or production of a biological pathway above-mentioned peptides. Diastereomers of a peptide are or molecule activity is between 25 to 100%. Even more pref obtained when the stereochemical or chiral center of one or erably the reduction of the activity or production of a biologi more amino acids is changed. The enantiomer has the oppo cal pathway or molecule activity is between 50 to 100%. site Stereochemistry at all chiral centers. 0272. As used herein “increase' is defined as an increase 0283. The term “prodrug” refers to any precursor com of the activity or production of a biological pathway or mol pound which is able to generate or to release the above ecule of between 10 to 100%. More preferably the increase of mentioned peptide under physiological conditions. Such pro the activity or production of a biological pathway or molecule drugs, i.e. Such precursor molecules are for instance larger US 2010/0204152 A1 Aug. 12, 2010 34 peptides which are selectively cleaved in order to form one of the two peptides (deviation +10%) were tested for activity the above-mentioned peptides. Further prodrugs are pro using the assays described in Examples 1 to 17. The tested tected amino acids having especially protecting groups at the peptides are all commercially available and are all known carboxylic acid and/or amino group. peptides and well described and characterized in the state of 0284 Suitable protecting groups for amino groups are the the art literature. The inventive peptide combination was pre benzyloxycarbonyl, t-butyloxycarbonyl (BOC), formyl, and pared by simply mixing the two commercially available pep acetyl or acyl group. Suitable protecting groups for the car tides in a molar ratio, for instance, between 0.9 to 1.1 and 1.1 boxylic acid group are esters such as benzyl esters or t-butyl to 0.9 (referred to as “approximately equimolar amounts’) or esterS. other ratios such as from 0.5-1.5 to 1.5-0.5. It has to be 0285. The present invention also includes the above pep mentioned that the biological data obtained with the peptide tides having amino acid Substitutions, deletions, additions, combinations in molar ratios between 0.4 to 1.6 mole (peptide the Substitutions and additions including the standard DandL 1 to peptide 2) and 1.6 to 0.4mol (peptide 1 to peptide 2) were amino acids and modified amino acids such as for example in general very similar to the biological data obtained with the amidated and acetylated amino acids, wherein the therapeutic equimolar peptide combinations so that in most cases the data activity of the base peptide sequence as shown above is main for the equimolar (from 0.9:1.1 to 1.1:0.9) combinations are tained. cited herein. Further data are presented only in these cases 0286. In the listed peptide sequences Ac' indicates an where the biological data of the peptide combinations with acetylated residue and “NH indicates an amidated residue, non equimolar amounts of the peptides differ more than 20% “cyclo” indicates a cyclic peptide, and “D’ indicates a D from the biological data of the equimolar combination. optical isomer. Deacetyled amino or NH-group refers to the 0298. The term "peptides' as used in the following free amino (—HH) group. examples refers to peptide 1, peptide 2 and the peptide com bination and the concentration of “10 micrograms per ml TABLE 3 refers to 10 ug peptide 1 per ml or 10 ug peptide 2 per ml or 10 ug peptide combination per ml. The following abbreviations are used for the 0299 Thus the term "peptides’ in the following examples common amino acids referred to herein. indicates that the test disclosed in the corresponding example Abbreviation Amino acid was conducted with peptide 1 alone and peptide 2 alone and Ala Alanine with the peptide combination generally in equimolar ratios Arg Arginine (molar ratio about 1:1 for peptide 1: peptide 2) if no other ASn Asparagine molar ratio is mentioned in the corresponding example. Asp Aspartic acid (Aspartate) Cys Cysteine Example 1 Gln Glutamine Glu Glutamic acid (Glutamate) Gly Glycine (0300 HIV-1 Experiments His Histidine (0301 CEM-SS cells were passaged in T-75 flasks prior to Ile Isoleucine use in the antiviral assay. On the day preceding the assay, the Leu Leucine cells were split 1:2 to assure they were in an exponential Lys Lysine growth phase at the time of infection. Total cell viability Met Methionine Phe Phenylalanine quantification was performed using a hemacytometer and Pro Proline trypan blue exclusion. Cell viability was greater than 95% for Pyl Pyrrolysine the cells to be utilized in the assay. The cells were resus Ser Serine Sec Selenocysteine pended at 5x10" cells/ml in tissue culture medium and added Thr Threonine to the peptides-containing microtiter plates in a Volume of 50 Trp Tryptophan microliters. Tyr Tyrosine 0302) The virus used was the lymphocytotropic strain Wal Valine ASX Aspartic acid or Asparagine HIV-1. Virus was obtained from NIH AIDS Research and Glx Glutamine or Glutamic acid Reference Reagent Program and was grown in CEM-SS cells Xaa Any amino acid for the production of stock virus pools. For each assay, a Xle Leucine or Isoleucine pre-titered aliquot of virus was removed from the freezer (-80°C.) and allowed to thaw slowly to room temperature in 0287. Some modified amino acids are indicated as fol a biological safety cabinet. The virus was resuspended and lows: diluted into tissue culture medium such that the amount of 0288 “D-2-Nal' is 2-naphthyl-D-alanine, virus added to each well in a volume of 50 microliters was the 0289) “SertBu' is t-butyl serine, amount determined to give between 85% to 95% cell killing 0290 “AZagly’ is aza glycine, after 6 days post-infection. TCIDso calculations by endpoint 0291 “Me” is methyl, titration in CEM-SS cells indicated that the multiplicity of 0292 Met(O) is methionine sulfoxide, infection was approximately 0.01. AZT (nucleoside reverse 0293 “Pyr” and “pGlu’ are pyroglutamic acid, transcriptase inhibitor; NRTI) and indinavir (protease inhibi 0294 “Tyr(SO3H) is sulphated tyrosine, tor; PI) were used as positive control antiviral compounds. 0295 “Tyr(Me)" is methyltyrosine, 0303 Plate Format 0296 “NHEt” is ethylamide. 0304 Each plate contained cell control wells (cells only), virus control wells (cells plus virus), drug cytotoxicity wells Examples (cells plus peptides only), peptide colorimetric control wells 0297. The peptides as listed above and the inventive pep (peptide only) as well as experimental wells (peptides—10 tide combination with approximately equimolar amounts of micrograms per ml plus cells plus virus). Samples were US 2010/0204152 A1 Aug. 12, 2010

evaluated for antiviral efficacy with triplicate measurements trol). A novel dye uptake assay was then employed to measure and with duplicate measurements to determine cellular cyto cell viability, which is used to calculate toxicity (% cell con toxicity, if detectable. trol). 0305 At assay termination, the plates were stained with 0313 Results from HBV experiments: Peptide 1 had no the soluble tetrazolium-based dye MTS (CelTiter 96 effect on inhibition of HBV replication on tested liver cells. Reagent, Promega) to determine cell viability and quantify Peptide 2 inhibited by 41.4% HBV replication as compared to peptides toxicity. MTS is metabolized by the mitochondrial the virus control infection. The peptide combination did not enzymes of metabolically active cells to yield a soluble for provide synergistic effects. In addition, the peptides of the mazan product, allowing the rapid quantitative analysis of invention did not show any significant inhibitory effects on cell viability and peptide cytotoxicity. This reagent is a stable, cell viability in these human liver cells. single solution that does not require preparation before use. At assay termination, 20-25 microliters of MTS reagent was Example 3 added per well and the microtiter plates were then incubated for 5 hours at 37° C., and 5% CO to assess cell viability. 0314 HCMV Experimental Assay System Adhesive plate sealers were used in place of lids, the sealed 0315 MRC-5 cells (human embryonal lung fibroblasts) plates were inverted several times to mix the soluble forma were obtained from the American Type Culture Collection Zan product and the plate was read spectrophotometrically at (ATCC CCL-171; Rockville, Md.) and grown in Eagle's 490/560 nm with a Molecular Devices Vmax plate reader. Minimum Essential Medium with Earle's BSS (EMEM) 0306 The overall assay performance was valid based supplemented with 10% fetal bovine serum (FBS), 0.1 mM upon judgment of the positive control compounds AZT and non-essential amino acids, 1.0 mMSodium pyruvate, 2.0 mM indinavir exhibiting the expected levels of antiviral activity. L-Glutamine, 100 units/ml Pencillin and 100 micrograms/ml Macroscopic observation of the cells in each well of the Streptomycin. Cells were split twice a week 1:2. microtiter plate confirmed the cytotoxicity results obtained 0316 HCMV strain AD 169 was obtained from ATCC following staining of the cells with the MTS metabolic dye. (ATCC VR-538). Virus stocks were prepared by infecting 0307 Results from HIV experiments: The peptide combi 80% confluent MRC-5 cells at a minimal multiplicity of nation of the invention showed no inhibition of HIV-1 activity infection in MRC-5 growth medium containing 2% FBS. on tested T-cells. In addition, the peptides of the invention did Monolayers were incubated at 37° C., 5% CO, until 90%- not show any significant inhibitory effects on cell viability in 95% viral cytopathic effect (CPE) was observed (10-13 days). these human T-cells. Culture medium was then collected from the cells, centri fuged at low speed to remove cellular debris, aliquoted in 1 ml Example 2 Volumes and stored at -80° C. as stock virus. 0308 HBV Experimental Assay System 0317 MRC-5 cells were seeded at 75,000 cells/well in 24 0309 HepG2-2.2.15 is a stable cell line containing the well plates using MRC-5 growth medium. The plates were hepatitis B virus (HBV) ayw strain genome (ATCC Cat. No. incubated overnight at 37° C., 5% CO. The following day, CRL-1 1997). Antiviral compounds blocking any late step of media was removed and 100 plaque forming units (pfu) of viral replication Such as transcription, translation, pregenome HCMV was added to the wells. Virus was allowed to adsorb encapsidation, reverse transcription, particle assembly and onto the cells for 1 hour at 37° C., 5% CO. Peptides were release can be identified and characterized using this cell line. diluted—10 micrograms per ml in assay medium contain In this assay, an active compound will reduce the production ing 0.5% Methylcellulose. After the incubation period, 1 ml of secreted HBV from cells, measured by utilizing real time of each peptide solution was added to the wells without aspi quantitative PCR (TaqMan) assay to directly and accurately rating the virus inoculums. The plates were incubated for measure HBV DNA copies. The analysis of this data allows to 7-10 days to allow for plaque formation. Ganciclovir was calculate: used as positive control. Cultures were examined microscopi 0310 Antiviral activity cally and toxicities were noted. The media was the aspirated 0311 Compound Cytotoxicity from the wells and the cells were fixed and stained using 20% 0312 HepG2-2.2.15 cells were plated in 96-well microti methanol containing Crystal Violet followed by enumeration ter plates. After 16-24 hours the confluent monolayer of of plaques by microscopic inspection. HepG2-2.2.15 cells was washed and the medium was 0318 For cytotoxicity testing, MRC-5 cells were seeded replaced with complete medium containing test peptides—10 at 2,500 cells/well in 96 well plates using growth medium. micrograms per ml in duplicate. Lamivudine (3TC) was The plates were incubated overnight at 37°C., 5% CO. The used as the positive control, while media alone was added to following day, peptides were added and tested in duplicates. the cells as a negative control (virus control). Three days later After a 6 days incubation period, cell viability was measured the culture medium was replaced with fresh medium contain using CellTiter96 Solution (Promega). Plates were incubated ing the peptides. Six days following the initial administration for additional 4 hours at 37°C. Adhesive plate sealers were of the peptides, the cell culture Supernatants was collected, used in place of lids, the sealed plates were inverted several treated with pronase and DNAse and then used in a real-time times to mix the soluble formazan product and the plate was quantitative TaqMan PCR assay. The PCR-amplified HBV read spectrophotometrically at 490/560 nm with a Molecular DNA was detected in real-time by monitoring increases in Devices Vmax plate reader. fluorescence signals that result from the exonucleolytic deg 0319. The overall assay performance was valid based radation of a quenched fluorescence probe molecule that upon judgment of the positive control compound Ganciclovir hybridizes to the amplified HBV DNA. For each PCR ampli exhibiting the expected levels of antiviral activity. Macro fication, a standard curve was simultaneously generated using scopic observation of the cells in each well of the microtiter dilutions of purified HBV DNA. Antiviral activity was calcu plate confirmed the cytotoxicity results obtained following lated from the reduction in HBV DNA levels (% virus con staining of the cells with the MTS metabolic dye. US 2010/0204152 A1 Aug. 12, 2010 36

0320 Results from HCMVassay: Peptide 1 and 2 did not 10 micrograms per ml ) were dispensed into wells in dupli inhibit HCMV plaque formation as compared to the virus cate. Then the wells were inoculated with 5x10 CFU/mL control experiment The peptide combination did not provide Streptococcus pneumoniae in 0.1 ml Volume. For control synergistic effects. In addition, the peptides of the invention purposes, each plate included 4 wells containing media with did not show any significant inhibitory effects on cell viability out bacterial inoculum and 4 wells containing medium with in these human lung cells. inoculum but without peptides. The plates were incubated for 12 hat 37°C., and read visually 18-24 hours post-incubation. Example 4 Growth control of Streptococcus pneumoniae was examined 0321 Methicillin Resistant Staphylococcus Aureus first to determine adequacy of media preparations and growth (MRSA) Assay conditions. Acceptable growth is defined as 22 mm wide 0322 The antibacterial assay was conducted using clear, button of cells at the bottom of each sample well, or obvious U-bottom 96-well microtiter plates. Cation-adjusted Muel turbidity in the culture supernatant. Test wells were examined ler-Hinton Broth (MHB) was used for testing MRSA. The and scored as positive/negative for activity. A positive score peptides of the invention (0.1 ml of each—10 micrograms per for activity is based on complete inhibition of macroscopic ml ) were dispensed into wells in duplicate. Then the wells growth of the test Streptococcus pneumoniae. were inoculated with 5x10 CFU/mL MRSA in 0.1 ml vol 0329 Results from Streptococcus pneumoniae assay: ume. For control purposes, each plate included 4 wells con Peptides of the invention and the peptide combination taining media without bacterial inoculum and 4 wells con showed no inhibitory effects on the growth of Streptococcus taining medium with inoculum but without peptides. The pneumoniae. plates were incubated for 12 h at 37° C., and read visually 18-24 hours post-incubation. Growth control of MRSA was Example 7 examined first to determine adequacy of media preparations and growth conditions. Acceptable growth is defined as 22 0330 Mycobacterium tuberculosis Assay mm wide button of cells at the bottom of each sample well, or 0331. The antibacterial assay was conducted using clear, obvious turbidity in the culture supernatant. Test wells were U-bottom 96-well microtiter plates. Middlebrook 7H12 assay examined and scored as positive/negative for activity. A posi medium was used for testing drug-resistant Mycobacterium tive score for activity is based on complete inhibition of tuberculosis. The peptides of the invention (0.1 ml of each— macroscopic growth of the test MRSA. 10 micrograms per ml ) were dispensed into wells in dupli 0323 Results from MRSA assay: Peptides of the inven cate. Then the wells were inoculated with 5x10 CFU/mL tion and the peptide combination showed no inhibitory effects Mycobacterium tuberculosis in 0.1 ml volume. For control on the growth of MRSA. purposes, each plate included 4 wells containing media with out bacterial inoculum and 4 wells containing medium with Example 5 inoculum but without peptides. The plates were incubated for seven days at 37° C., and read visually thereafter. Growth 0324 Pseudomonas aeruginosa Assay control of Mycobacterium tuberculosis was examined first to 0325 The antibacterial assay was conducted using clear, determine adequacy of media preparations and growth con U-bottom 96-well microtiter plates. Cation-adjusted Muel ditions. Acceptable growth is defined as 22 mm wide button ler-Hinton Broth (MHB) was used for testing Pseudomonas of cells at the bottom of each sample well, or obvious turbidity aeruginosa. The peptides of the invention (0.1 ml of each— in the culture Supernatant. Test wells were examined and 10 micrograms per ml ) were dispensed into wells in dupli scored as positive/negative for activity. A positive score for cate. Then the wells were inoculated with 5x10 CFU/mL activity is based on complete inhibition of macroscopic Pseudomonas aeruginosa in 0.1 ml Volume. For control pur growth of the test Mycobacterium tuberculosis. The drug poses, each plate included 4 wells containing media without resistant Mycobacterium tuberculosis that was used in the bacterial inoculum and 4 wells containing medium with assay is resistant against following medicaments: para-ami inoculum but without peptides. The plates were incubated for nosalicylic acid (PAS), streptomycin and isoniazid (INH). 12 hat 37°C., and read visually 18-24 hours post-incubation. 0332 Results from Mycobacterium tuberculosis assay: Growth control of Pseudomonas aeruginosa was examined Peptides of the invention and the peptide combination first to determine adequacy of media preparations and growth showed no inhibitory effects on the growth of Mycobacterium conditions. Acceptable growth is defined as 22 mm wide tuberculosis. button of cells at the bottom of each sample well, or obvious turbidity in the culture supernatant. Test wells were examined and scored as positive/negative for activity. A positive score Example 8 for activity is based on complete inhibition of macroscopic 0333 Cell Cycle Assay growth of the test Pseudomonas aeruginosa. 0334 Human A549 cells (carcinomic human alveolar 0326 Results from Pseudomonas aeruginosa assay: Pep basal epithelial cells) were utilized in the experiments tides of the invention and the peptide combination showed no employing the Propidium iodide cell cycle assay. The eukary inhibitory effects on the growth of Pseudomonas aeruginosa. otic cell cycle is a series of events that take place in a cell Example 6 leading to its replication. 0335 The regulation of the cell cycle involves steps cru 0327 Streptococcus pneumoniae Assay cial to the cell, including detecting and repairing genetic 0328. The antibacterial assay was conducted using clear, damage, and provision of various checks to prevent uncon U-bottom 96-well microtiter plates. Cation-adjusted Muel trolled cell division. The molecular events that control the cell ler-Hinton Broth (MHB) was used for testing Streptococcus cycle are ordered and directional; that is, each process occurs pneumoniae. The peptides of the invention (0.1 ml of each— in a sequential fashion. US 2010/0204152 A1 Aug. 12, 2010 37

0336. The cell cycle consists of four distinct phases: G Example 10 phase, S phase, G2 phase (collectively known as interphase) and M phase. M phase is itself composed of two tightly (0343 B Cell Proliferation Assay coupled processes: mitosis, in which the cell's chromosomes 0344 Human Peripheral Blood Mononuclear Cells are divided between the two daughter cells, and cytokinesis, (PBMC) were obtained from normal human donors. The B in which the cell's cytoplasm divides forming distinct cells. cell proliferation was induced by stimulation of the cells with Activation of each phase is dependent on the proper progres the B cell mitogen Staphylococcus aureus Cowans I (SAC) sion and completion of the previous one. Cells that have plus Interleukin-2, either in the absence (positive prolifera temporarily or reversibly stopped dividing are said to have tion control), or in the presence of test peptides—10 micro entered a state of quiescence called Go phase. The relatively grams per ml to examine their effects on the B cell response. brief Mphase consists of nuclear division and cytoplasmic 10/well PBMC were plated in 96-well microtiter plates and division. The first phase within interphase, from the end of the assayed in duplicate with the peptides. Cell cultures were previous M. phase till the beginning of DNA synthesis is incubated at 37°C. for 3 days in a 5% CO incubator and were called G (G indicating gap or growth). During this phase the thereafter pulsed with 1 microCi/well H-thymidine for addi biosynthetic activities of the cell resume at a high rate. This tional 12 hours of culture. At the end of incubation time, the phase is marked by Synthesis of various enzymes that are plates were harvested and the cells counted by liquid scintil required in S phase, mainly those needed for DNA replica lation for the incorporation of H-thymidine as a measure of tion. The ensuing S phase starts when DNA synthesis com B cell proliferation. mences; when it is complete, all of the chromosomes have 0345 Results from B cell proliferation assay: Peptides of been replicated. The cell then enters the G phase, which lasts the invention and the peptide combination showed no signifi until the cell enters mitosis. Significant protein synthesis cant inhibitory effects on the proliferation of specifically occurs during this phase, mainly involving the production of stimulated human B-cells. microtubules, which are required during the process of mito sis. Inhibition of protein synthesis during G2 phase prevents Example 11 the cell from undergoing mitosis. 0337 Disregulation of the cell cycle components may lead 0346 Phagocytosis Assay to tumor formation. 0347 RAW264.7 (Mouse leukaemic monocyte macroph 0338 Propidium iodide is an intercalating agent and a age cell line) cells were obtained from ATCC and grown in fluorescent molecule that can be used to stain DNA. Cells RPMI 1640 medium containing 10% FBS. Cells were incu were incubated for 24 hours with test peptides—10 micro bated in 12x75 mm tubes at 37°C. with test peptides—10 grams per ml or left untreated. After that cells were micrograms per ml for 30 min prior to adding Fluorescein trypsinized, suspended in medium+10% FCS, centrifuged labeled Escherichia coli bacteria as the agent to be ingested. (1000 rpm, 5min), and the cell pellet resuspended in PBS (1 After the cells were incubated for additional 60 min at 37° C. ml). The cells were pipetted into 2.5 ml absolute EtOH (final and allowed to ingest the Fluorescein-labeled Escherichia concentration approx. 70%) and incubated on ice for 15 min. coli bacteria, cells were fixed with 1% paraformaldehyde. Thereafter, cells were pelleted at 1500 rpm for 5 min and The samples were then analyzed by flow cytometry to deter resuspended in Propidium iodide solution in PBS. After incu mine the amount of phagocytosis as a function of brightness bation for 40 min at 37°C., cells were analyzed in the FACS. (the greater the phagocytic activity, the more fluorescence in 0339 Results from cell cycle assay: Peptides of the inven the macrophage population). Data are reported as % positive tion and the peptide combination showed no inhibitory or and the mean fluorescence intensity (MFI) of positively irregular effects on the cell cycle of the tested human lung stained cells. cells. 0348 Results from phagocytosis assay: Peptide 1 of the invention showed 22.9% increase and the peptide 2 showed Example 9 no inhibitory or activating effect on the phagocytic activity of murine macrophages. The peptide combination (peptide 1:peptide 2 (1.10 mole:0.90 mole) did not show any inhibi (0340 T Cell Proliferation Assay tory or activating effect on the phagocytic activity of murine (0341 Human Peripheral Blood Mononuclear Cells macrophages. (PBMC) were obtained from normal human donors. The T cell proliferation was induced by stimulation of the cells with the T cell mitogen phytohemagglutinin (PHA), either in the Example 12 absence (positive proliferation control), or in the presence of test peptides—10 micrograms per ml to examine their 0349 Apoptosis Induction Assay effects on the T cell proliferating response. 10/well PBMC 0350 Human A549 cells (carcinomic human alveolar were plated in 96-well microtiter plates and assayed in dupli basal epithelial cells) were utilized in the experiments cate with the peptides. Cell cultures were incubated at 37°C. employing the Annexin-5 apoptosis assay. Annexin-5 is a for 3 days in a 5% CO incubator and were thereafter pulsed member of a highly conserved protein family that binds acidic with 1 microCi/well H-thymidine for additional 12 hours of phospholipids in a calcium-dependent manner. Annexin-5 culture. At the end of incubation time, the plates were har possesses a high affinity for phosphatidylserine. Phosphati vested and the cells counted by liquid scintillation for the dylserine is translocated from the inner side of the plasma incorporation of H-thymidine as a measure of T cell prolif membrane to the outer layer when cells undergo death by eration. apoptosis or cell necrosis and serves as a signal by which cell 0342. Results from T cell proliferation assay: Peptides of destined for death are recognized by phagocytes. Test pep the invention and the peptide combination showed no signifi tides—10 micrograms per ml were exposed for 24 hours to cant inhibitory effects on the proliferation of specifically the A549 cells before they were analyzed for signs of apop stimulated human T-cells. tosis. US 2010/0204152 A1 Aug. 12, 2010 38

0351 Results from apoptosis induction assay: Peptides of Example 15 the invention and the peptide combination showed no signifi cant induction of apoptosis on human lung cells. 0358 TNF Alpha Production Assay 0359 Human Peripheral Blood Mononuclear Cells Example 13 (PBMC) were obtained from normal human donors. The macrophages were prepared by adherence of PBMC to the 0352 Apoptosis Prevention Assay plastic wells of the plates. After 8 days in culture in the 0353 Human A549 cells (carcinomic human alveolar basal epithelial cells) were utilized in the experiments presence of recombinant human macrophage-colony Stimu employing the Annexin-5 apoptosis assay. Annexin-5 is a lating factor at 2 ng/ml, differentiated macrophages were member of a highly conserved protein family that binds acidic preincubated with test peptides—10 micrograms per ml for phospholipids in a calcium-dependent manner. Annexin-5 30 min, followed by in-well stimulation by the addition of possesses a high affinity for phosphatidylserine. Phosphati lipopolysaccharide at a final concentration of 200 ng/ml. Not dylserine is translocated from the inner side of the plasma stimulated macrophages served as negative background con membrane to the outer layer when cells undergo death by trol. apoptosis or cell necrosis and serves as a signal by which cell 0360. After overnight incubation, supernatants from the destined for death are recognized by phagocytes. A549 cells control and LPS-stimulated cultures were harvested and were pretreated for 30 min with test peptides—10 micro assayed for TNF alpha production employing a TNF alpha grams per ml followed by the exposure to C2 ceramide. specific ELISA. Ceramide mediates cell apoptosis through the activation of 0361 Results from TNF alpha assay: Peptide 1 inhibited the mitogen activating protein kinase (MAPK) and the stress by 22.4% the LPS-induced TNF-alpha production in human activated kinase (JNK/SAPK). C2 ceramide is a synthetic, macrophages, peptide 2 did not induced or inhibit the LPS membrane soluble analog of ceramide. induced TNF-alpha production in human macrophages and 0354 Results from apoptosis prevention assay: Peptides the peptide combination (peptide 1:peptide 2 (0.95 mole: 1.05 of the invention and the peptide combination showed no mole) did not show any effect on the induction or inhibition of significant protection against ceramide-induced apoptosis on the LPS-induced TNF-alpha production in human macroph human lung cells. ageS. Example 14 Example 16 0355 Th1/Th2 Cytokine Profiling Assay 0356. The Balbic mice (originated in 1923, it is a popular 0362 Endothelial Cell Migration Assay strain and is used in many different research disciplines. Also 0363 Endothelial cell migration is a prerequisite for the classified as an inbred from the production of 20 or more process of neo-vascularization orangiogenesis which is cru Successive brother-sister matings, the Balb/c mouse is albino cial for on-site recruitment of blood vessel formation. Pri and small in size) were immunized on Days 1, 15, and 29 with mary Human endothelial cells (HUVEC) were seeded in Ovalbumin (Ovalbumin is the main protein found in egg insert chambers with 3 micrometer pore size of multi-tran white, commonly used to stimulate an immunological reac swell plate for 6 hours at 37° C. in Endothelial Cell Basal tion intest animals) in PBS (5 micrograms/injection). On day Medium (EBM) supplemented with 0.1% bovine serum albu 50, spleens of the mice were harvested (3 weeks after last min. Thereafter, designated concentration of testing pep boost with Ovalbumin). Cells were cultured (2x10/well in tides—10 micrograms per ml was added in duplicate wells. triplicate) and incubated with culture medium or test pep The endothelia were allowed to migrate for 22 hours at 37°C., tides—10 micrograms per ml for 30 min. Thereafter, addi then, migrated cells were fixed and stained with Hoechst tional Ovalbumin was added to the cells at 10 micrograms/ml 33342 dye. Images of 3 fields per insert were taken and the for in vitro restimulation of the cells. 72 hours later, cell number of migrated cells per field were quantified using the Supernatants were harvested and assayed using the Becton ImageProPlus software. Data were analyzed for the average Dickinson Mouse Th1/Th2 Cytokine CBA Kit. This kit can number of the migrated cells and standard deviation of six be used to measure Interleukin-2 (IL-2), Interleukin-4 (IL-4), data points for each treatment condition. Active test peptides Interleukin-5 (IL-5), Interferon-Y (IFN-Y), and Tumor Necro against HUVEC migration was determined based on 50% sis Factor-O. (TNF-C.) protein levels in a single sample. The kit inhibition of migrated cells as compared with the control. performance has been optimized for analysis of physiologi Statistic p values were computed using the Student's t-test. cally relevant concentrations (pg/ml levels) of specific cytok 0364 Results from endothelial cell migration assay: Pep ine proteins in tissue culture Supernatants and serum samples. tide 1 inhibited by 35% the migration of human endothelial 0357 Results from Th1/Th2 Cytokine assay: cells, peptide 2 inhibited by 7% the migration of human

TNF-a spleen IFNY spleen IL-4 spleen IL-5 spleen cells: TH1 cells: TH1 IL-2 spleen cells; TH2 cells: TH2 response (% of response (% of cells (% of response (% response (% of Compound control) control) control) of control) control) Ala-Val-Pro-Tyr- 86.6 52.4 55.7 O.O 53.0 Pro-Gln-Arg-OH Gluten Exorphin C 126.2 53.9 124.0 94.1 86.6 combination 99.3 56.2 81.5 544 73.3 US 2010/0204152 A1 Aug. 12, 2010 39 endothelial cells and the peptide combination (peptide 1: pep 0374. Then soya oil and lecithin are added to the milk tide 2 (0.95 mole: 1.05 mole) inhibited by 26% the tube for substitute composition at 60° C. The milk composition is mation endothelial cells. allowed to stand 30 min at 55° C. After pasteurization, the peptide 1 of the invention is added in liquid or powderform in Example 17 Such a quantity that the milk composition obtained comprises an amount of 5-50 micrograms, preferably 10-40 micrograms 0365 Endothelial Tube Formation Assay per 100 ml of milk composition. Optionally peptide 2 could 0366. The endothelial tube formation assay is based on the be added in similar or Smaller amounts to the obtained com ability of endothelial cells to form three-dimensional capil position. lary-like tubular structures when cultured on a gel of base ment membrane extract. The endothelial tube formation Example 19 assay represents a powerful model for studying inhibition and induction of angiogenesis. Pre-labeled HUVEC with Calcein 0375 Gel Formulation AM were seeded in a 96-well culture plate coated with extra 0376 0.5g of peptide 1 cellular metrix (Chemicon international Cat. ECM625) and 0377 1.6 g of isopropanol treated with test peptides—10 micrograms per ml in full 0378 1.0 g of glycerol growth medium. Positive control was vehicle only. The 0379 1.6 g of polyoxyethylene-polyoxypropylene endothelial cells were allowed to form tubes for 20 hours and copolymer 12500 (Pluronic F127) were then examined under an inverted fluorescent micro (0380 5.3g of water Scope. Duplicate wells for each treatment were photographed 0381 are mixed for 10 minutes and then heated to 85°C. and quantitatively analyzed for an average tubule length using under continuous stirring for 15 minutes. The solution is image analysis software ImageProPlus. Raw data were cooled to room temperature under stirring. During the cooling expressed as average tubule lengths in pixelsistandard devia phase the solution begins to gel at a temperature of about 45° tion. Statistic p values were computed using the Student's C. to form a clear gel. The gel contains 5% of the peptide 1 for t-teSt. medical use. Optionally peptide 2 could be added in an 0367 Results from endothelial tube formation assay: Pep amount form 0.01 to 0.5g. tide 1 inhibited by 18% the tube formation of endothelial Example 20 cells, peptide 2 inhibited by 100% the tube formation of endothelial cells and the peptide combination (peptide 1: pep 0382 Lotion Formulation tide 2 (0.95 mole: 1.05 mole) inhibited by 97% and the peptide (0383 0.5g of peptide 1 combination (peptide 1:peptide 2 (0.50 mole: 1.50 mole) 0384 1.9 g of isopropanol inhibited by 100% the tube formation of endothelial cells. (0385) 1.0 g of dimethylisosorbide 0386 1.0 g of polyoxyethylene-polyoxypropylene Example 18 copolymer 12500 (Pluronic F127) (0387 5.6 g of water 0368 Mother Milk Formulation 0388 are stirred and heated at 50° C., until a clear solution 0369 Methods to prepare mother milk or artificial mother has been formed. Then the composition is cooled to room milk formulations or mother milk substitutes are described in temperature under stirring. The lotion contains 5% of peptide WO03043429, U.S. Pat. No. 5,962,062, WO0030461, 1 for medical use. Optionally peptide 2 could be added in an EP0527283, EP0832565 amount form 0.01 to 0.5g. 0370. One example of an artificial mother milk or mother milk substitute formulation is provided in the following while Example 21 also the other formulations disclosed in the above mentioned 0389 Gel Formulation references can be used and are included herewith by refer 0390 0.3 g of peptide 1 CCC. 0391 0.3 g of peptide 2 0371. The milk substitute contains, by weight, approxi 0392 1.6 g of isopropanol mately 15% skimmed milk solids, approximately 75% dem 0393 1.0 g of glycerol ineralized water, approximately 9%. Soya oil, approximately 0394 1.6 g of polyoxyethylene-polyoxypropylene 0.02% of carrageenates, 0.2% lecithin, and approximately copolymer 12500 (Pluronic F127) 0.2% of disodium hydrogenphosphate. 0395. 5.3g of water 0372. In a first step, the solubilizing aqueous medium is 0396 are mixed for 10 minutes and then heated to 85°C. produced, comprises, by weight, approximately 75% of under continuous stirring for 15 minutes. The solution is water, approximately 0.02% of carrageenate and approxi cooled to room temperature under stirring. During the cooling mately 0.2% of disodium hydrogenphosphate. phase the solution begins to gel at a temperature of about 45° 0373 The skimmed milk powder is then added to the C. to form a clear gel. The gel contains 6% of the peptide solution for 10 min at 60° C. and dissolved in the liquid. combination for medical use.

SEQUENCE LISTING

<16 Os NUMBER OF SEO ID NOS: 2

<21 Os SEQ ID NO 1 &211s LENGTH: 7 212s. TYPE: PRT US 2010/0204152 A1 Aug. 12, 2010 40

- Continued <213> ORGANISM: Homo sapiens <4 OOs, SEQUENCE: 1 Ala Val Pro Tyr Pro Glin Arg 1. 5

SEQ ID NO 2 LENGTH: 5 TYPE PRT ORGANISM: Homo sapiens <4 OOs, SEQUENCE: 2 Tyr Pro Ile Ser Lieu 1. 5

1-15. (canceled) 23. The method of claim 22, wherein the pharmaceutical 16. A pharmaceutical composition comprising a combina composition comprises a second peptide consisting of the tion of a first peptide and a second peptide or salts or hydrates sequence Tyr-Pro-Ile-Ser-Leu-OH (SEQID NO:2). thereof, wherein the first peptide consists of the sequence 24. The method of claim 22, wherein the cancer, the Ala-Val-Pro-Tyr-Pro-Gln-Arg-OH (SEQ ID NO:1) and the autoimmune disease, fibrotic disease, inflammatory disease, neurodegenerative disease, infectious disease, lung disease, second peptide consists of the sequence Tyr-Pro-Ile-Ser-Leu heart and vascular disease or metabolic disease is selected OH (SEQID NO:2). from vasculitis and excessive angiogenesis in autoimmune 17. The pharmaceutical composition of claim 16, wherein disorders, systemic Sclerosis, multiple Sclerosis, Sjögren's the first and second peptide are contained in the combination disease, vascular malformations in blood and lymph vessels, in an amount from 30% by weight of the first peptide to 70% DiGeorge syndrome, hereditary haemorrhagic telangiectasia, by weight of the second peptide, to 70% by weight of the first cavernous hemangioma, cutaneous hemangioma, lymphatic peptide to 30% by weight of the second peptide. malformations, transplant arteriopathy, atherosclerosis, vas 18. The pharmaceutical composition of claim 16, wherein cular anastomoses, adipose tissue in obesity, chronic allograft said composition is incorporated in a nutritional formulation. rejections, skin diseases, psoriasis, warts, allergic dermatitis, scar keloids, pyogenic granulomas, blistering disease, Kaposi 19. The pharmaceutical composition of claim 18, wherein sarcoma in AIDS patients, systemic Sclerosis, eye diseases, the nutritional formulation is an artificial mother milk formu persistent hyperplastic vitreous syndrome, diabetic retinopa lation or mother milk substitute suitable for oral administra thy, retinopathy of prematurity, choroidal neovascularization, tion to newborns, toddlers and infants. lung diseases, pulmonary hypertension, asthma, nasal polyps, 20. The pharmaceutical composition of claim 16, wherein rhinitis, chronic airway inflammation and obstruction, cystic said composition is prepared as a lyophilized formulation or fibrosis, acute lung injury, bronchiolitis obliterans organizing a buffered liquid formulation. pneumonia, gastrointestinal tract diseases, inflammatory 21. The pharmaceutical composition of claim 16, wherein bowel disease, periodontal disease, ascites, peritoneal adhe said composition comprises at least one pharmaceutically sions, liver cirrhoses, reproductive system diseases, acceptable carrier, cryoprotectant, lyoprotectant, excipient or endometriosis, uterine bleeding, ovarian cysts, ovarian hyper stimulation, bone and joint diseases, arthritis and synovitis, diluent. osteomyelitis, osteophyte formation, HIV-induced bone mar 22. A method of treatment of cancer, autoimmune disease, row angiogenesis, kidney diseases and early diabetic nephr fibrotic disease, inflammatory disease, neurodegenerative opathy. disease, infectious disease, lung disease, heart and vascular 25. The method of claim 22, wherein the pharmaceutical disease and metabolic disease, the method comprising, composition is administered by intravenous administration, administering to a patient in need thereof, a therapeutically oral administration, or administration by inhalation. effective amount of a pharmaceutical composition com 26. The method of claim 22, wherein the pharmaceutical prising a first peptide consisting of the sequence Ala composition is administered as a lyophilized formulation or Val-Pro-Tyr-Pro-Gln-Arg-OH (SEQID NO:1) or a salt as a buffered liquid formulation. or hydrate thereof, wherein administration of the phar maceutical composition treats said diseases. c c c c c