US 2010O210539A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0210539 A1 BeVec et al. (43) Pub. Date: Aug. 19, 2010

(54) USE OF PEPTIDE LL-37 ASATHERAPEUTIC A6IP 29/00 (2006.01) AGENT A6IP 25/00 (2006.01) A6IP II/00 (2006.01) (76) Inventors: Dorian Bevec, Germering (DE); A6IP 9/00 (2006.01) Fabio Cavalli, Beckenried (CH): A6IP3/00 (2006.01) Vera Cavalli, Muzzano (CH): Gerald Bacher, Germering (DE) Correspondence Address: (52) U.S. Cl...... 514/12:530/324 WINSTEAD PC P.O. BOX SO784 DALLAS, TX 75201 (US) (57) ABSTRACT (21) Appl. No.: 12/677,802 The present invention is directed to the use of the peptide compound Leu-Leu-Gly-Asp-Phe-Phe-Arg-Lys-Ser-Lys (22) PCT Filed: Sep. 9, 2008 Glu-Lys-Ile-Gly-Lys-Glu-Phe-Lys-Arg-Ile-Val-Gln-Arg Ile-Lys-Asp-Phe-Leu-Arg-Asn-Leu-Val-Pro-Arg-Thr-Glu (86). PCT No.: PCT/EP2008/007931 Ser-NH2 as a therapeutic agent for the prophylaxis and/or treatment of cancer, autoimmune diseases, fibrotic diseases, S371 (c)(1), inflammatory diseases, neurodegenerative diseases, infec (2), (4) Date: Mar. 11, 2010 tious diseases, lung diseases, heart and vascular diseases and metabolic diseases. Moreover the present invention relates to (30) Foreign Application Priority Data pharmaceutical compositions preferably in form of a lyophi lisate or liquid buffer solution or artificial mother milk for Sep. 11, 2007 (EP) ...... O7017765.4 mulation or mother milk Substitute containing the peptide Leu-Leu-Gly-Asp-Phe-Phe-Arg-Lys-Ser-Lys-Glu-Lys-Ile Publication Classification Gly-Lys-Glu-Phe-Lys-Arg-Ile-Val-Gln-Arg-Ile-Lys-Asp (51) Int. Cl. Phe-Leu-Arg-Asn-Leu-Val-Pro-Arg-Thr-Glu-Ser-NH A6IK 38/16 (2006.01) optionally together with at least one pharmaceutically accept C07K I4/00 (2006.01) able carrier, cryoprotectant, lyoprotectant, excipient and/or A6IP35/00 (2006.01) diluent. US 2010/0210539 A1 Aug. 19, 2010

USE OF PEPTIDE LL-37 ASATHERAPEUTIC erative diseases, infectious diseases, lung diseases, heart and AGENT vascular diseases and metabolic diseases. Also disclosed are pharmaceutical formulations preferably in form of a lyophi lisate or liquid buffer solution or artificial mother milk for 0001. The present invention is directed to the use of the mulation containing the inventive peptide. The peptide is peptide compound Leu-Leu-Gly-Asp-Phe-Phe-Arg-Lys-Ser especially useful for prophylaxis and/or treatment of B cell Lys-Glu-Lys-Ile-Gly-Lys-Glu-Phe-Lys-Arg-Ile-Val-Gln lymphomas, Epstein-Barr virus induced mononucleosis, sys Arg-Ile-Lys-Asp-Phe-Leu-Arg-Asn-Leu-Val-Pro-Arg-Thr temic lupus erythematosis, rheumatoid arthritis, autoimmune Glu-Ser-NH. (LL-37) as a therapeutic agent for the lymphoproliferative disease, multiple Sclerosis, psoriasis, prophylaxis and/or treatment of cancer, autoimmune dis myasthenia gravis, Hashimoto's thyroiditis, lupus nephritis, eases, fibrotic diseases, inflammatory diseases, neurodegen dermatomyositis, Sjogren's syndrome, Sydenham's chorea, erative diseases, infectious diseases, lung diseases, heart and lupus nephritis, rheumatic fever, polyglandular syndromes, vascular diseases and metabolic diseases. bullous pemphigoid, diabetes mellitus, Henoch-Schonlein purpura, post-streptococcal nephritis, erythema nodosum, BACKGROUND OF THE INVENTION Takayasu's arteritis, Addison's disease, Crohn's disease, Alzheimer's disease, sarcoidosis, ulcerative colitis, erythema 0002 The identification of a therapeutic compound effec multiforme, IgA nephropathy, polyarteritis nodosa, ankylos tive for the prophylaxis and/or treatment of a disease can be ing spondylitis, Goodpasture's syndrome, thromboangitis based on the activity of the compound in a biological assay. A ubiterans, primary biliary cirrhosis, thyrotoxicosis, Sclero biological assay that mimics a disease causative mechanism derma, pulmonary fibrosis, Sarcoidosis, chronic active hepa can be used to test the therapeutic activity of a candidate titis, polymyositis, dermatomyositis, polychondritis, pam peptide. phigus Vulgaris, Wegener's granulomatosis, membranous 0003. The causative mechanism of many diseases is the over activity of a biological pathway. A peptide that can nephropathy, amyotrophic lateral Sclerosis, tabes dorsalis, reduce the activity of the biological pathway can be effective giant cell arteritis, polymyalgia, pernicious anemia, rapidly in the prophylaxis and/or treatment of the disease caused by progressive glomerulonephritis, fibrosing alveolitis, thromb the over activity of the biological pathway. Similarly the ocytopenias, rejection of any organ transplant or graft-Versus causative mechanism of many diseases is the over production host disease after a bone marrow transplant and other diseases of a biological molecule. A peptide that can reduce the pro which are described in the following. duction of the biological molecule or block the activity of the Cancer, Tumors, Proliferative Diseases, Malignancies and over produced biological molecule can be effective in the their Metastases prophylaxis and/or treatment of the disease caused by the 0008. The term "cancer as used herein refers also to over production of the biological molecule. tumors, proliferative diseases, malignancies and their 0004 Conversely, the causative mechanism of many dis metastases. Examples for cancer diseases are adenocarci eases is the under activity of a biological pathway. A peptide noma, choroidal melanoma, acute leukemia, acoustic neuri that can increase the activity of the biological pathway can be noma, ampullary carcinoma, anal carcinoma, astrocytoma, effective in the prophylaxis and/or treatment of the disease basal cell carcinoma, pancreatic cancer, desmoid tumor, blad caused by the under activity of the biological pathway. Also der cancer, bronchial carcinoma, non-Small cell lung cancer similarly the causative mechanism of many diseases is the (NSCLC), breast cancer, Burkitt's lymphoma, corpus cancer, under production of a biological molecule. A peptide that can CUP-syndrome (carcinoma of unknown primary), colorectal increase the production of the biological molecule or mimic cancer, Small intestine cancer, Small intestinal tumors, ova the biological activity of the under produced biological mol rian cancer, endometrial carcinoma, ependymoma, epithelial ecule can be effective in the prophylaxis and/or treatment of cancertypes, Ewing's tumors, gastrointestinal tumors, gastric the disease caused by the under production of the biological cancer, gallbladder cancer, gallbladder carcinomas, uterine molecule. cancer, cervical cancer, cervix, glioblastomas, gynecologic 0005. It is the object of the present invention to provide a tumors, ear, nose and throat tumors, hematologic neoplasias, compound for the prophylaxis and/or treatment of cancer, hairy cell leukemia, urethral cancer, skin cancer, skin testis autoimmune diseases, fibrotic diseases, inflammatory dis cancer, brain tumors (gliomas), brain metastases, testicle can eases, neurodegenerative diseases, infectious diseases, lung cer, hypophysis tumor, carcinoids, Kaposi's sarcoma, laryn diseases, heart and vascular diseases and metabolic diseases. geal cancer, germ cell tumor, bone cancer, colorectal carci 0006. The object of the present invention is solved by the noma, head and neck tumors (tumors of the ear, nose and teaching of the independent claims. Further advantageous throat area), colon carcinoma, craniopharyngiomas, oral can features, aspects and details of the invention are evident from cer (cancer in the mouth area and on lips), cancer of the the dependent claims, the description, and the examples of the central nervous system, liver cancer, liver metastases, leuke present application. mia, eyelid tumor, lung cancer, lymph node cancer (Hodgkin’s/Non-Hodgkin’s), lymphomas, stomach cancer, DESCRIPTION OF THE INVENTION malignant melanoma, malignant neoplasia, malignant tumors gastrointestinal tract, breast carcinoma, rectal cancer, 0007. The present invention relates to the use of the pep medulloblastomas, melanoma, meningiomas, Hodgkin's dis tide Leu-Leu-Gly-Asp-Phe-Phe-Arg-Lys-Ser-Lys-Glu-Lys ease, mycosis fungoides, nasal cancer, neurinoma, neuroblas Ile-Gly-Lys-Glu-Phe-Lys-Arg-Ile-Val-Gln-Arg-Ile-Lys toma, kidney cancer, renal cell carcinomas, non-Hodgkin’s Asp-Phe-Leu-Arg-Asn-Leu-Val-Pro-Arg-Thr-Glu-Ser-NH lymphomas, oligodendroglioma, esophageal carcinoma, (LL-37), its use as a therapeutic in medicine and for the osteolytic carcinomas and osteoplastic carcinomas, osteosa prophylaxis and/or treatment of cancer, autoimmune dis rcomas, ovarial carcinoma, pancreatic carcinoma, penile can eases, fibrotic diseases, inflammatory diseases, neurodegen cer, plasmocytoma, squamous cell carcinoma of the head and US 2010/0210539 A1 Aug. 19, 2010 neck (SCCHN), prostate cancer, pharyngeal cancer, rectal opathy (BSE), candidiasis, capillariasis (Capillaria infec carcinoma, retinoblastoma, vaginal cancer, thyroid carci tion), chronic fatigue syndrome (CFS), Chagas disease 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 peptide of the present invention was tested Cryptosporidium infection (cryptosporidiosis), Culex mos using the assays described in Examples 1-7, 9-17 for their quito (West Nile virus vector), cyclosporiasis (Cyclospora effect as active therapeutic agents in the prophylaxis and/or infection), cysticercosis (neurocysticercosis), Cytomegalovi treatment of cancer, proliferative diseases, tumors and their rus infection, Dengue/Dengue fever, Dipylidium infection metaStaSeS. (dog and cat flea tapeworm), Ebola virus hemorrhagic fever, encephalitis, Entamoeba coli infection, Entamoeba dispar Infectious Disease infection, Entamoeba hartmanni infection, Entamoeba his 0010. The immune system in higher vertebrates represents tolytica infection (amebiasis), Entamoeba polecki infection, the first line of defense against various antigens that can enter enterobiasis (pinworm infection), enterovirus infection (non the vertebrate body, including microorganisms such as bac polio), Epstein-Barr virus infection, Escherichia coli infec teria, fungi and viruses that are the causative agents of a tion, foodborne infection, foot and mouth disease, fungal variety of diseases. dermatitis, gastroenteritis, group A Streptococcal disease, 0.011 Despite large immunization programs, viral infec group B streptococcal disease, Hansen's disease (leprosy), tions, such as influenza virus, human immunodeficiency virus Hantavirus pulmonary syndrome, head lice infestation (pe (“HIV), herpes simplex virus (“HSV”, type 1 or 2), human diculosis), Helicobacter pylori infection, hematologic dis papilloma virus (“HPV, type 16 or 18), human cytomega ease, Hendra virus infection, hepatitis (HCV. HBV), herpes lovirus (“HCMV) or human hepatitis B or C virus (“HBV, Zoster (shingles), HIV Infection, human ehrlichiosis, human Type B; "HCV, type C) infections, remain a serious source parainfluenza virus infection, influenza, isosporiasis (Isos of morbidity and mortality throughout the world and a sig pora infection), Lassa fever, leishmaniasis, Kala-azar (Kala nificant cause of illness and death among people with azar, Leishmania Infection), lice (body lice, head lice, pubic immune-deficiency associated with aging or different clinical lice), Lyme disease, malaria, Marburg hemorrhagic fever, conditions. Although antiviral chemotherapy with com measles, meningitis, mosquito-borne diseases, Mycobacte pounds such as amantadine and rimantadine have been shown rium avium complex (MAC) infection, Naegleria infection, to reduce the duration of symptoms of clinical infections (i.e., nosocomial infections, nonpathogenic intestinal ameobae influenza infection), major side effects and the emergence of infection, onchocerciasis (river blindness), opisthorciasis drug-resistant variants have been described. New classes of (Opisthorcis infection), parvovirus infection, plague, Pneu antiviral agents designed to target particular viral proteins mocystis carinii pneumonia (PCP), polio, Q fever, rabies, Such as influenza neuraminidase are being developed. How respiratory syncytial virus (RSV) Infection, rheumatic fever, ever, the ability of viruses to mutate the target proteins rep Rift Valley fever, river blindness (onchocerciasis), rotavirus resents an obstacle for effective treatment with molecules infection, roundworm infection, salmonellosis, salmonella which selectively inhibit the function of specific viral enteritidis, Scabies, Shigellosis, shingles, sleeping sickness, polypeptides. Thus, there is need for new therapeutic strate Smallpox, Streptococcal Infection, tapeworm infection (Tae gies to prevent and treat viral infections. nia infection), tetanus, toxic shock syndrome, tuberculosis, 0012. Additionally, there is a need for new therapies for ulcers (peptic ulcer disease), Valley fever, Vibrio para the prevention and treatment of bacterial infections, espe haemolyticus, infection, Vibrio vulnificus infection, viral cially bacterial infections caused by multiple drug resistant hemorrhagic fever, warts, waterborne infectious diseases, bacteria. Currently, bacterial infections are treated with vari West Nile virus infection (West Nile encephalitis), whooping ous antibiotics. Although antibiotics have and can be effective cough, yellow fever. in the treatment of various bacterial infections, there are a 0015. Another aspect of the present invention is directed to number of limitations to the effectiveness and safety of anti the use of the peptide for prophylaxis and/or treatment of biotics. For example, some individuals have an allergic reac prion diseases. tion to certain antibiotics and other individuals suffer from 0016 Prions are infectious agents which do not have a serious side effects. Moreover, continued use of antibiotics nucleic acid genome. It seems that a protein alone is the for the treatment of bacterial infections contributes to forma infectious agent. A prion has been defined as 'small proteina tion of antibiotic-resistant strains of bacteria. ceous infectious particle which resists inactivation by proce 0013 Another aspect of the present invention is directed to dures that modify nucleic acids”. The discovery that proteins the use of the peptide for prophylaxis and/or treatment of alone can transmit an infectious disease came as a consider infectious diseases including opportunistic infections. able Surprise to the Scientific community. Prion diseases are 0014 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 US 2010/0210539 A1 Aug. 19, 2010

(BSE) of cattle and the new variant of Creutzfeld-Jakob dis 0023. It has long been known that immune complex for ease (v0.JD) caused by BSE as well as scrapie of animals. mation plays a role in the etiology and progression of autoim Examples of human prion diseases include kuru, sporadic mune disease. For example, inflammation in patients with Creutzfeldt-Jakob disease (sCJD), familial CJD (f(JD), arthritis has long been considered to involve phagocytosis by iatrogenic CJD (iCJD), Gerstmann-Straussler-Scheinker leukocytes of complexes of antigen, antibody and comple (GSS) disease, fatal familial insomnia (FFI), and especially ment-immune complexes. However, only now it is being rec the new variant CJD (nvCJD or vCJD). ognized that inflammation caused by immune complexes in 0017. The name “prion' is used to describe the causative the joints (arthritis), the kidneys (glomerulonephritis), and agents which underlie the transmissible spongiform encepha blood vessels (vasculitis) is a major cause of morbidity in lopathies. A prion is proposed to be a novel infectious particle autoimmune diseases. Increased immune complex formation that differs from viruses and viroids. It is composed solely of correlates with the presence of antibodies directed to self or one unique protein that resists most inactivation procedures so-called autoantibodies, and the presence of the latter can Such as heat, radiation, and proteases. The latter characteristic also contribute to tissue inflammation either as part of an has led to the term protease-resistant isoform of the prion immune complex or unbound to antigen (free antibody). In protein. The protease-resistant isoform has been proposed to Some autoimmune diseases, the presence of free autoanti slowly catalyze the conversion of the normal prion protein body contributes significantly to disease pathology. This has into the abnormal form. been clearly demonstrated for example in SLE (anti-DNA 0018. The term “isoform' in the context of prions means antibodies), immune thrombocytopenia (antibody response two proteins with exactly the same amino acid sequence that directed to platelets), and to a lesser extent rheumatoid arthri can fold into molecules with dramatically different tertiary tis (IgG reactive rheumatoid factor). The important role of structures. The normal cellular isoform of the prion protein immune complexes and free autoantibodies is further dem (PrP) has a high C-helix content, a low B-sheet content, and onstrated by the fact that successful treatment of certain is sensitive to protease digestion. The abnormal, disease autoimmune diseases has been achieved by the removal of causing isoform (PrP) has a lower C-helix content, a much immune complexes and free antibody by means of specific higher B-sheet content, and is much more resistant to protease immunoadsorption procedures. For example, the use of an digestion. apheresis procedure in which immune complexes and anti 0019. As used herein the term “prion diseases’ refers to bodies are removed by passage of a patient’s blood through an transmissible spongiform encephalopathies. Examples for immunoaffinity column was approved by the U.S. FDA in prion diseases comprise scrapie (sheep, goat), transmissible 1987 for immune thrombocytopenia (ITP) and in 1999 for mink encephalopathy (TME, mink), chronic wasting disease rheumatoid arthritis. However, currently there is no approved (CWD; muledeer, deer, elk), bovine spongiform encephal method for the treatment of autoimmune diseases which opathy (BSE: cows, cattles), Creutzfeld-Jacob Disease facilitates the elimination of immune complexes and autoan (CJD), variant CJD (VCJD), sporadic Creutzfeldt-Jakob dis tibodies by administration of a drug. ease (SCJD), familial CJD (f(JD), iatrogenic CJD (iCJD. 0024. Another aspect of the etiology and progression of Gerstmann-Straussler-Scheinker, syndrome (GSS), fatal autoimmune disease is the role of proinflammatory cytokines. familial insomnia (FFI), and kuru. Preferred are BSE, VCJD. Under normal circumstances, proinflammatory cytokines and CJD. such as tumor necrosis factor C. (TNFC.) and interleukin-1 0020. The peptide of the present invention was tested (IL-1) play a protective role in the response to infection and using the assays described in Examples 1-7 for their effect as cellular stress. However, the pathological consequences active therapeutic agents in the prophylaxis and/or treatment which result from chronic and/or excessive production of of infectious diseases and disorders. TNFC. and IL-1 are believed to underlie the progression of many autoimmune diseases such as rheumatoid arthritis, Autoimmune Disease Crohn's disease, inflammatory bowel disease, and psoriasis. 0021 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 0025 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 0022. 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 0026. 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 US 2010/0210539 A1 Aug. 19, 2010

diseases like autoimmune disorders could be prevented by 0038 Examples of neurological autoimmune disorders interfering with the mechanisms of leukocyte extravasation. are Guillain-Barré syndrome, IgM gammopathy-associated Significant progress in elucidating the molecular basis of the neuropathy, Lambert-Eaton syndrome, Miller-Fisher syn 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 0039 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 0040. 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 0041. 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 0027. 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 0028. 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 0042. The peptide of the present invention was tested molysis bullosa aquisita (EBA), acquired angioedema, her using the assays described in Examples 14-15 for their effect pes gestationes, hypocomplementemic urticarial vasculitis as active therapeutic agents in the prophylaxis and/or treat syndrome (HUVS), linear IgA-dermatosis, and pemphigus. ment of autoimmune diseases and disorders. 0029. Examples of hematological autoimmune diseases are autoimmune hemolytic anemia, autoimmune neutrope Fibrotic Disease nia, Evans syndrome, inhibitor hemophilia, idiopathic throm 0043. Fibrosis or fibrosis associated disorder affects the bocytopenial purpura (ITP) and pernicious anemia. liver, epidermis, endodermis, muscle, tendon, cartilage, 0030 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, 0031 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 0032 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. Meniere. 0044 Fibrosis is generally characterized by the pathologic 0033 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 0034 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 0035 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 0036) 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, 0037. 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 US 2010/0210539 A1 Aug. 19, 2010

systemic lupus, and the like), cutiskeloid formation, progres diverse models of fibrosis in various tissues. In view of these sive systemic sclerosis (PSS), primary Sclerosing cholangitis properties, the persistence or prolonged Survival of the myo (PSC), liver fibrosis, liver cirrhosis, renal fibrosis, pulmonary fibroblast may be the key to understanding why certain forms fibrosis, cystic fibrosis, chronic graft versus host disease, of lung injury may result in progressive disease, terminating Scleroderma (local and systemic), Grave's opthalmopathy, in end stage disease. diabetic retinopathy, glaucoma, Peyronie's disease, penis 0048 Although pulmonary fibrosis has diverse etiologies, fibrosis, urethrostenosis after a test using a cystoscope, inner there is a common feature characteristic of this process, accretion after Surgery, Scarring, myelofibrosis, idiopathic namely, the abnormal deposition of extracellular matrix that retroperitoneal fibrosis, peritoneal fibrosis from a known eti effaces the normal lung tissue architecture. A key cellular ology, drug induced ergotism, fibrosis incident to benign or Source of this matrix is the mesenchymal cell population that malignant cancer, fibrosis incident to microbial infection occupies much of the fibrotic lesion during the active period (e.g., viral, bacterial, parasitic, fungal, etc.), Alzheimer's dis 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 0045 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, Sclerodactyl), 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 following myocardial infarction, central nervous system Increased TGF-B Family Levels in Fibrotic Diseases fibrosis following a stroke or neuro-degenerative diseases 0049. The transforming growth factor-3 (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 induced). bleomycin-induced lung fibrosis and human fibrotic lung tis Sue shows enhanced TGF-B gene and protein expression. Increased Number of Activated Myofibroblasts in Fibrotic Several lines of evidence suggest that TGF-B is a central Diseases regulator of pulmonary fibrosis. Several animal models over expressing TGF-B showed extensive progressive fibrosis but 0046. The emergence and disappearance of the myofibro limited inflammation, indicating that TGF-B may play a pre blast appears to correlate with the initiation of active fibrosis dominant role in the progression of pulmonary fibrosis. and its resolution, respectively. In addition, the myofibroblast Therapeutic efforts are therefore focusing on inhibition of has many phenotypic features, which embody much of the TGF-B activity, for instance by anti-TGF-31-antibodies, or pathologic alterations in fibrotic tissue, e.g. lung tissue. These modulators of TGF-31 such as pirfenidone. Pirfenidone features would seem to argue for an important role for the inhibits TGF-B1 gene expression in vivo resulting in inhibi myofibroblast in the pathogenesis of fibrosis, e.g. lung fibro tion of TGF-31-mediated collagen synthesis and appears to sis, Furthermore, the persistence of the myofibroblast may slow progression of IPF in patients. Other novel, promising herald progressive disease, and, conversely, its disappearance antifibrotic agents include relaxin (inhibits TGF-3-mediated may be an indicator of resolution. This in turn suggests that overexpression of collagen and increases collagenases), future therapeutic strategies targeting the myofibroblast Suramin (inhibits growth factors), prostaglandin E2 (inhibits would be productive. collagen production) and lovastatin (blocks formation of 0047 Patients usually exhibit evidence of active fibrosis granulation tissue by induction of fibroblast apoptosis). with increased numbers of activated fibroblasts, many of 0050 Diseases involving the lung associated with which have the phenotypic characteristics of myofibroblasts. increased levels of TGF-B include chronic lung disease of At these sites, increased amounts of extracellular matrix prematurity, idiopathic pulmonary fibrosis, rapid progressive deposition are evident with effacement of the normal alveolar pulmonary fibrosis, giant-cell interstitial pneumonia, acute architecture: Animal model studies show the myofibroblast to rejection after lung transplantation, cytomegalovirus pneu be the primary Source of type I collagen gene expression in monitis, after lung transplantation, bronchiolitis obliterans, active fibrotic sites. In vitro studies show differentiation of asbestosis, coal worker's pneumoconiosis, silicosis, histiocy these cells from fibroblasts under the influence of certain tosis, sarcoidosis, eosinophilic granuloma, Scleroderma, sys cytokines but indicate their susceptibility to nitric oxide temic lupus erythematosus, lymphangioleiomyomatosis, mediated apoptosis. In addition to promoting myofibroblast central fibrosis inpulmonary adenocarcinoma, cystic fibrosis, differentiation, transforming growth factor-f1 (TGF-31) pro chronic obstructive lung disease, and asthma. vides protection against apoptosis. Thus, this well-known fibrogenic cytokine is important both for the emergence of the Increased TNF-C. Levels in Fibrotic Diseases myofibroblast and its survival againstapoptotic stimuli. This 0051. 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 US 2010/0210539 A1 Aug. 19, 2010

mice, which either overexpress or display a deficiency of this activation or release from extracellular matrix or carrier pro cytokine. Mice transgenically modified to overexpress teins before they can exert their activity. In fact, the pro TNF-C. develop lung fibrosis. In contrast, mice null for teolytic activity processing of several key factors involved in TNF-C. show marked resistance to bleomycin induced fibro the pathogenesis of pulmonary fibrosis Such as insulin-like sis. TNF-C. can stimulate fibroblast replication and collagen growth factor (IGF). TGF-B and TNF-C. occur through the synthesis in vitro, and pulmonary TNF-C. gene expression actions of MMPs, thereby activating or releasing them from rises after administration of bleomycin in mice. Soluble inhibitory protein-protein interactions. For example, IGFs in TNF-C. receptors reduce lung fibrosis in murine models and vivo are sequestered by six high affinity IGF binding proteins pulmonary overexpression of TNF-C. in transgenic mice is (IGFBPs 1-6), preventing their ability to interact with IGF characterized by lung fibrosis. In patients with CFA or asbes receptors. Studies examining adults and children IPF and tosis, bronchoalveolar lavage fluid-derived macrophages interstitial lung disease show that beside IPF, IGFBP-3 and release increased amounts of TNF-C. compared with controls. IFPB-2 levels are increased in IPF BAL fluid. MMPs have 0052 Increased TNF-C. may induce fibrosis or fibrosis recently been shown to regulate the cleavage of IGF binding associated conditions affecting any tissue including, for proteins, thereby liberating the complexed ligand to affect example, fibrosis of an internal organ, a cutaneous or dermal IGF actions in target cells. Observations have also shown that fibrosing disorder, and fibrotic conditions of the eye. Fibrosis the gelatinases, MMP-9 and MMP-2 may be involved in of internal organs (e.g., liver, lung, kidney, heart blood ves proteolytic activation of latent TGF-B complexes. Further sels, gastrointestinal tract) occurs in disorders such as pulmo more, the MMP inhibitor Batimastat reduces MMP-9 activity nary fibrosis, idiopathic fibrosis, autoimmune fibrosis, in BAL fluid, which was associated with decreased amount of myelofibrosis, liver cirrhosis, veno-occlusive disease, mesan TGF-B and TNF-C. gial proliferative glomerulonephritis, crescentic glomerulo 0054 Pulmonary fibrosis can be an all too common con nephritis, diabetic nephropathy, renal interstitial fibrosis, sequence of an acute inflammatory response of the lung to a renal fibrosis in Subjects receiving cyclosporin, allograft host of inciting events. Chronic lung injury due to fibrotic rejection, HTV associated nephropathy. Other fibrosis-asso changes can result from an identifiable inflammatory event or ciated disorders include systemic sclerosis, eosinophilia-my an insidious, unknown event. The inflammatory process can algia syndrome, and fibrosis-associated CNS disorders such include infiltration of various inflammatory cell types, such as as intraocular fibrosis. Dermal fibrosing disorders include, for neutrophils and macrophages, the secretion of inflammatory example, Scleroderma, morphea, keloids, hypertrophic scars, cytokines and chemokines and the Secretion of matrix remod familial cutaneous collagenoma, and connective tissue nevi eling proteinases. of the collagen type. Fibrotic conditions of the eye include conditions such as diabetic retinopathy, post-Surgical scarring Increased CCL 18 Levels in Fibrotic Diseases (for example, after glaucoma filtering Surgery and after crossed-eyes (strabismus) Surgery), and proliferative vitreo 0055. The expression and regulation of cysteine-cysteine retinopathy. Additional fibrotic conditions that may be treated (CC) chemokine ligand 18 (CCL18), a marker of alternative by the methods of the present invention may result, for activation, by human alveolar macrophages (AMs) is example, from rheumatoid arthritis, diseases associated with increased in patients with pulmonary fibrosis and correlates prolonged joint pain and deteriorated joints; progressive sys negatively with pulmonary function test parameters. Thus, temic sclerosis, polymyositis, dermatomyositis, eosinophilic CCL18 is an ideal diagnostic marker for pulmonary fibrosis. fasciitis, morphea, Raynaud's syndrome, and nasal polyposis. 0056. The peptide of the present invention was tested using the assays described in Examples 14-15 for their effect Increased Matrix Metalloproteases Levels in Fibrotic Dis as active therapeutic agents in the prophylaxis and/or treat CaSS ment of fibrotic diseases and disorders. 0053. The abnormal extracellular matrix (ECM) remodel Inflammatory Disease ing observed in the lungs of patients with interstitial pulmo nary fibrosis (IPF) is due, at least in part, to an imbalance 0057 Inflammation is the final common pathway of vari between matrix metalloproteases (MMPs) and tissue inhibi ous insults, such as infection, trauma, and allergies to the tor of metalloproteinases (TIMPs). Normal lung fibroblasts human body. It is characterized by activation of the immune do not make MMP-9 in vitro, whereas fibroblasts from IPF system with recruitment of inflammatory cells, production of lungs strongly express MMP-9. In addition, fibroblasts from pro-inflammatory cells and production of pro-inflammatory patients with IPF express increased levels of all TIMPs. In this cytokines. Most inflammatory diseases and disorders are setting, TIMPs may play a role in apoptosis in some cell characterized by abnormal accumulation of inflammatory populations. In vitro studies of alveolar macrophages cells including monocytes/macrophages, granulocytes, obtained from untreated patients with idiopathic pulmonary plasma cells, lymphocytes and platelets. Along with tissue fibrosis showed marked increase in MMP-9 secretion com endothelial cells and fibroblasts, these inflammatory cells pared to macrophages collected from healthy individuals. In release a complex array of lipids, growth factors, cytokines animals models of bleomycin-induced pulmonary fibrosis and destructive enzymes that cause local tissue damage. MMPs have been shown to be elevated in bronchoalveolar 0058. One form of inflammatory response is neutrophilic lavage (BAL) fluid. Indeed, a synthetic inhibitor of MMP, inflammation which is characterized by infiltration of the Batimastat, has been shown to significantly reduce bleomy inflamed tissue by neutrophil polymorphonuclear leukocytes cin-induced lung fibrosis, again pointing to the importance of (PMN), which are a major component of the host defense. MMPs in the development of this fibrotic disease in the lung. Tissue infection by extracellular bacteria represents the pro A number of studies have shown that the actions of MMPs can totype of this inflammatory response. On the other hand, result in the release of growth factors and cytokines. These various non-infectious diseases are characterized by profibrotic factors require proteolytic processing for their extravascular recruitment of neutrophils. This group of US 2010/0210539 A1 Aug. 19, 2010

inflammatory diseases includes chronic obstructive pulmo arthritis, asthma, atherosclerosis; atopic dermatitis; autoim nary disease, adult respiratory distress syndrome, some types mune hepatitis; autoimmune hemolytic anemia; autoimmune of immune-complex alveolitis, cystic fibrosis, bronchitis, hepatitis: Behcet’s disease; Bell's palsy, bullous pemphigoid; bronchiectasis, emphysema, glomerulonephritis, rheumatoid cerebral ischemia; chronic obstructive pulmonary disease; arthritis, gouty arthritis, ulcerative colitis, certain dermatoses cirrhosis: Cogan's syndrome; contact dermatitis: COPD; 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 0059 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; 0060 TNF-C. has several biologic activities that are impor uveitis; vasculitis; and Wegener's granulomatosis. tant in homeostasis as well as in pathophysiological condi 0062. 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 0061 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, US 2010/0210539 A1 Aug. 19, 2010

lichen spinulosus, nummular dermatitis, pyoderma gan 0079 conditions associated with acute trauma such as grenosum, sarcoidosis, Subcorneal pustular dermatosis, urti cerebral injury following stroke-sensory loss, motor caria, and transient acantholytic dermatosis. loss, cognitive loss; 0063. By “proliferative skin disease' is meant a benign or 0080 heart tissue injury due to myocardial ischemia:— malignant disease that is characterized by accelerated cell pain, shortness of breath; division in the epidermis or dermis. Examples of proliferative 0081 lung injury such as that which occurs in adult skin diseases are psoriasis, atopic dermatitis, nonspecific der respiratory distress syndrome:—shortness of breath, matitis, primary irritant contact dermatitis, allergic contact hyperventilation, decreased oxygenation, pulmonary dermatitis, basal and squamous cell carcinomas of the skin, infiltrates; lamellar ichthyosis, epidermolytic hyperkeratosis, premalig 0082 inflammation accompanying infection, such as nant keratosis, acne, and seborrheic dermatitis. As will be sepsis, septic shock, toxic shock syndrome:—fever, res appreciated by one skilled in the art, a particular disease, piratory failure, tachycardia, hypotension, leukocytosis; disorder, or condition may be characterized as being both a 0.083 other inflammatory conditions associated with proliferative skin disease and an inflammatory dermatosis. particular organs or tissues, such as: An example of Such a disease is psoriasis. (i) nephritis (e.g., glomeralonephritis):—oliguria, abnormal 0.064 Symptoms and signs of inflammation associated urinalysis; with specific conditions include: (ii) inflamed appendix:—fever, pain, tenderness, leukocyto 0065 rheumatoid arthritis: pain, swelling, warmth S1S, and tenderness of the involved joints; generalized and (iii) gout:- pain, tenderness, Swelling and erythema of the morning stiffness; involved joint, elevated serum and/or urinary uric acid; 0.066 insulin-dependent diabetes mellitus-insulitis; this (iv) inflamed gallbladder:—abdominal pain and tenderness, condition can lead to a variety of complications with an fever, nausea, leukocytosis; inflammatory component, including:—retinopathy, (V) congestive heart failure:—shortness of breath, rales, neuropathy, nephropathy; coronary artery disease, peripheral edema; peripheral vascular disease, and cerebrovascular dis (vi) Type II diabetes:—end organ complications including ease, cardiovascular, ocular, renal, and peripheral vascular disease; 0067 autoimmune thyroiditis: weakness, constipa (vii) lung (pulmonary) fibrosis:—hyperventilation, shortness tion, shortness of breath, puffiness of the face, hands and of breath, decreased oxygenation; feet, peripheral edema, bradycardia; (viii) vascular disease, such as atherosclerosis and resteno 0068 multiple sclerosis:—spasticity, blurry vision, ver sis: pain, loss of sensation, diminished pulses, loss of func tigo, limb weakness, paresthesias; tion; and 0069 uveoretinitis:—decreased night vision, loss of (ix) alloimmunity leading to transplant rejection: pain, ten peripheral vision; derness, fever. 0070 lupus erythematosus: joint pain, rash, photo I0084. A human peptide is “active' in an inflammatory sensitivity, fever, muscle pain, puffiness of the hands and disease if the inhibition is >50% in one of the assays described feet, abnormal urinalysis (hematuria, cylinduria, pro below. Inhibition (as percentage) was calculated using the teinuria), glomerulonephritis, cognitive dysfunction, following formula: % inhibition-(1-concentration of cytok vessel thrombosis, pericarditis; ines in Sample/concentration of cytokines in positive con 0071 scleroderma: Raynaud's disease; swelling of trol)x100. The positive control refers to stimulated samples, the hands, arms, legs and face; skin thickening; pain, not treated with substances. Swelling and stiffness of the fingers and knees, gas trointestinal dysfunction, restrictive lung disease; peri B Lymphocyte Proliferation carditis; renal failure; I0085 Lymphocytes enable the body to remember antigens 0072 other arthritic conditions having an inflammatory and to distinguish self from nonself (foreign). Lymphocytes component such as rheumatoid spondylitis, osteoarthri circulate in the bloodstream and lymphatic system and move tis, septic arthritis and polyarthritis:—fever, pain, Swell into tissues as needed. The immune system can remember ing, tenderness; every antigen encountered because lymphocytes live a long 0073 other inflammatory brain disorders, such as men time—for years or even decades. When lymphocytes encoun ingitis, Alzheimer's disease, AIDS dementia encephali ter an antigen for the second time, they respond quickly, tis: photophobia, cognitive dysfunction, memory loss; vigorously, and specifically to that particular antigen. Lym 0074 other inflammatory eye inflammations, such as phocytes include B lymphocytes, T lymphocytes, and natural retinitis:—decreased visual acuity; killer cells (which are involved in nonspecific immunity). 0075 inflammatory skin disorders, such as, eczema, other dermatites (e.g., atopic, contact), psoriasis, burns B Lymphocytes induced by UV radiation (sun rays and similar UV I0086 B lymphocytes (B cells) are formed in the bone Sources):—erythema, pain, Scaling, Swelling, tender marrow. B lymphocytes have particular sites (receptors) on neSS, their surface where specific antigens can attach. When a B 0076 inflammatory bowel disease, such as Crohn's dis lymphocyte encounters an antigen, the antigen attaches to the ease, ulcerative colitis: pain, diarrhea, constipation, receptor, stimulating the B lymphocyte to change into a rectal bleeding, fever, arthritis; plasma cell. Plasma cells produce antibodies. These antibod 0077 asthma:—shortness of breath, wheezing: ies are specific to the antigen that stimulated their production. 0078 other allergy disorders, such as allergic rhini I0087. The human body makes millions of different types tis:—Sneezing, itching, runny nose of B cells each day that circulate in the blood and lymph US 2010/0210539 A1 Aug. 19, 2010

performing the role of immune surveillance. Each B cell has disease, Alzheimer's disease, sarcoidosis, ulcerative colitis, a unique receptor protein (referred to as the B cell receptor erythema multiforme, IgA nephropathy, polyarteritis nodosa, (BCR)) on its surface that will bind to one particular antigen. ankylosing spondylitis, Goodpasture's syndrome, throm The BCR is a membrane-bound immunoglobulin, and it is boangitis ubiterans, primary biliary cirrhosis, thyrotoxicosis, this molecule that allows the distinction of B cells from other Scleroderma, chronic active hepatitis, polymyositisfdermato types of lymphocyte, as well as being the main protein myositis, polychondritis, pamphigus Vulgaris, Wegener's involved in B cell activation. Once a B cell encounters its granulomatosis, membranous nephropathy, amyotrophic lat cognate antigen and receives an additional signal from a T eral Sclerosis, tabes dorsalis, giant cell arteritis/polymyalgia, helper cell, it can further differentiate into one of the two pernicious anemia, rapidly progressive glomerulonephritis, types of B cells listed below. The B cell may either become fibrosing alveolitis, thrombocytopenias. one of these cell types directly or it may undergo an interme diate differentiation step, the germinal center reaction, where T Lymphocyte Proliferation the B cell will hypermutate the variable region of its immu noglobulin gene (“somatic hypermutation') and possibly 0096. Lymphocytes enable the body to remember antigens undergo class Switching. and to distinguish self from nonself (foreign). Lymphocytes 0088 Plasma B cells (also known as plasma cells) are circulate in the bloodstream and lymphatic system and move large B cells that have been exposed to antigen and are pro into tissues as needed. The immune system can remember ducing and secreting large amounts of antibodies, which every antigen encountered because lymphocytes live a long assist in the destruction of microbes by binding to them and time—for years or even decades. When lymphocytes encoun making them easier targets for phagocytes and activation of ter an antigen for the second time, they respond quickly, the complement system. vigorously, and specifically to that particular antigen. Lym I0089 Memory B cells are formed from activated B cells phocytes include B lymphocytes, T lymphocytes, and natural that are specific to the antigen encountered during the primary killer cells (which are involved in nonspecific immunity). immune response. These cells are able to live for a long time, and can respond quickly following a second exposure to the T Lymphocytes same antigen. 0097 T cells play the most important, central role in cell 0090. On the other hand, B cells also play a key role in the mediated immunity. They can be distinguished from other initiation of the pathogenesis of many immune-mediated dis lymphocyte types such as B cells and NK cells by the pres eases, such as autoimmune and atopic diseases. Therefore, ence of a special receptor on their cell surface called the T cell targeting B-lymphocytes provides a rationale for refining receptor (TCR). All T cells originate from hematopoietic strategies to treat Such diseases in their early stages for long stem cells in the bone marrow. Progenitors derived from term clinical benefits and minimal negative side effects. hematopoietic stem cells populate the thymus and expand by 0091 B cells are involved in the pathogenesis of autoim cell division to generate a large population of immature thy mune diseases at several levels, even in diseases generally mocytes. The earliest thymocytes express neither CD4 nor viewed as T cell mediated. In addition to being precursors for CD8, and are therefore classified as double-negative (CD4 antibody-secreting plasma cells, B cells also play a crucial CD8) cells. As they progress through their development they role as antigen-presenting cells (APC) in autoimmune dis become double-positive thymocytes (CD4"CD8), and ease, as shown in animal models of diabetes, rheumatoid finally mature to single-positive (CD4"CD8 or CD4-CD8") arthritis (RA) and systemic lupus erythematosus (SLE). In thymocytes (T cells) that are then released from the thymus to murine models of autoimmune thyroid disease (AITD), B peripheral tissues. cells are shown to act as APCs and are a prerequisite for the 0.098 Activation of T cells occurs through the engagement initiation of the disease process. of both the T cell receptor and CD28 on the T cell by the Major 0092 B cells are further involved in autoimmunity by histocompatibility complex peptide and B7 family members virtue of their early in the disease important production of on the antigen presenting cells (APC), respectively. Both are autoantibodies. Therefore, potential effector mechanisms of required for production of an effective immune response; in B cell Suppressing therapy early in autoimmune diseases the absence of CD28 co-stimulation, T cell receptor signal comprise: ling alone results in anergy. The signalling pathways down (0093. Impairment of the B cell function as APCs, stream from both CD28 and the T cell receptor involve bio thereby providing less stimuli to, for example, CD4+T- logical activity of many different proteins. helper cell proliferation and cytokine production (0099. The first signal is provided by binding of the T cell 0094) Impairment of production of disease-specific receptor to a short peptide presented by the major histocom memory B cells, plasma cells and autoantibodies patibility complex (MHC) on another cell. This ensures that 0095 Finally, hyperproliferation of B cells is relevant to only a T cell with a TCR specific to that peptide is activated. cancers like B cell lymphomas, viral infections like Epstein The partner cell is usually a professional APC, usually a Barr virus induced mononucleosis, or early stages of autoim dendritic cell in the case of naive responses, although B cells mune diseases. Representative autoimmune diseases include and macrophages can be important APCs. The peptides pre systemic lupus erythematosis, rheumatoid arthritis, autoim sented to CD8+ T cells by MHC class I molecules are 8-9 mune lymphoproliferative disease, multiple Sclerosis, psoria amino acids in length; the peptides presented to CD4+ cells sis, myasthenia gravis, Hashimoto's thyroiditis, lupus nephri by MHC class II molecules are longer, as the ends of the tis, dermatomyositis, Sjogren's syndrome, Sydenham's binding cleft of the MHC class II molecule are open. chorea, lupus nephritis, rheumatic fever, polyglandular syn 0100. The second signal comes from co-stimulation, in dromes, bullous pemphigoid, diabetes mellitus, Henoch which surface receptors on the APC are induced by a rela Schonlein purpura, post-Streptococcal nephritis, erythema tively small number of stimuli, usually products of pathogens, nodosum, Takayasu's arteritis, Addison's disease, Crohn's but sometimes breakdown products of cells, such as necrotic US 2010/0210539 A1 Aug. 19, 2010

bodies or heat-shock proteins. The only co-stimulatory recep but are found at their highest abundance in the gut mucosa, tor expressed constitutively by naive T cells is CD28, so within a population of lymphocytes known as intraepithelial co-stimulation for these cells comes from the CD80 and lymphocytes (IELS). The antigenic molecules that activate Yö CD86 proteins on the APC. The second signal enables the T T cells are still widely unknown. However, Y& T cells are not cell to respond to an antigen. Without it, the T cell becomes MHC restricted and seem to be able to recognise whole pro anergic, and it becomes more difficult for it to be activated in teins rather than requiring peptides to be presented by MHC future. This mechanism prevents inappropriate responses to molecules on antigen presenting cells. self, as self-peptides will not usually be presented with suit able co-stimulation. Deregulation of that process leads to T Cell Diseases autoimmune disorders. 0108. The most human autoimmune diseases are specific 0101 Different subsets of T cells have been described, antigen-driven T-cell diseases. T-cell clones responding to each with a distinct function: specific antigenic epitopes are responsible for the propaga 0102 Helper T cells (T cells) are the “middlemen” of the tion of these diseases. Similarly, specific antigen-driven adaptive immune system. Once activated, they divide rapidly T-cell responses are responsible for the rejection of organ and secrete cytokines that regulate or “help' the immune allografts after transplantation. response. Depending on the cytokine signals received, these 0109 T cell immunosuppression involves an act that cells differentiate into T1, T2, T17, or one of other Sub reduces the activation or efficacy of the T cells. Deliberately sets, which secrete different cytokines. CD4+ cells associated induced T cell immunosuppression is generally done to pre with MHC class II. vent the body from rejecting any organ transplant, treating (0103 Cytotoxic T cells (CTLs) destroy virally infected graft-Versus-host disease after a bone marrow transplant, or cells and tumor cells, and are also implicated in transplant for the treatment of autoimmune diseases. rejection. These cells are also known as CD8" T cells (asso ciated with MHC class I), since they express the CD8 glyco 0110. The peptide of the present invention was tested protein at their Surface. using the assays described in Examples 1-7, 9-17 for their 0104 Memory T cells are a subset of antigen-specific T effect as active therapeutic agents in the prophylaxis and/or cells that persist long-term after an infection has resolved. treatment of inflammatory diseases and disorders. They quickly expand to large numbers of effector T cells upon re-exposure to their cognate antigen, thus providing the Neurodegenerative Disease immune system with “memory against past infections. 0111. The present invention also relates generally to the Memory T cells comprise two subtypes: central memory T fields of neurology and psychiatry and to methods of protect cells (T cells) and effector memory T cells (T cells). ing the cells of a mammalian central nervous system from Memory cells may be either CD4+ or CD8+. damage or injury. I0105 Regulatory T cells (T cells) are crucial for the 0112 Injuries or trauma of various kinds to the central maintenance of immunological tolerance. Their major role is nervous system (CNS) or the peripheral nervous system to shut down T cell-mediated immunity toward the end of an (PNS) can produce profound and long-lasting neurological immune reaction and to Suppress auto-reactive T cells that and/or psychiatric symptoms and disorders. One form that escaped the process of negative selection in the thymus. Two this can take is the progressive death of neurons or other cells major classes of CD4+ regulatory T cells have been of the central nervous system (CNS), i.e., neurodegeneration described, including the naturally occurring T reg cells and the or neuronal degeneration. adaptive T cells. Naturally occurring T cells (also known 0113 Neuronal degeneration as a result of for example: as CD4"CD25"FoxP3T cells) arise in the thymus, Alzheimer's disease, multiple Sclerosis, cerebral-vascular whereas the adaptive T cells (also known as Tr1 cells or Th3 accidents (CVAS)/stroke, traumatic brain injury, spinal cord cells) may originate during a normal immune response. Natu injuries, degeneration of the optic nerve, e.g., ischemic optic rally occurring T cells can be distinguished from other T neuropathy or retinal degeneration and other central nervous cells by the presence of an intracellular molecule called system disorders is an enormous medical and public health FoxP3. Mutations of the FOXP3 gene can prevent regulatory problem by virtue of both its high incidence and the frequency T cell development, causing the fatal autoimmune disease of long-term sequelae. Animal studies and clinical trials have called immunodysregulation polyendocrinopathy enteropa shown that amino acid transmitters (especially glutamate), thy X-linked syndrome (IPEX). oxidative stress and inflammatory reactions contribute 0106 Natural Killer T cells (NKT cells) are a special kind strongly to cell deathin these conditions. Upon injury or upon of lymphocyte that bridges the adaptive immune system with ischemic insult, damaged neurons release massive amounts the innate immune system. Unlike conventional T cells, that of the neurotransmitter glutamate, which is excitotoxic to the recognize peptide antigen presented by major histocompat Surrounding neurons. Glutamate is a negatively charged ibility complex (MHC) molecules, NKT cells recognize gly amino acid that is an excitatory synaptic transmitter in the colipid antigen presented by a molecule called CD1d. Once mammalian nervous system. Although the concentration of activated, these cells can perform functions ascribed to both glutamate can reach the millimolar range in nerve terminals T, and T cells (i.e., cytokine production and release of its extracellular concentration is maintained at a low level to cytolytic/cell killing molecules). prevent neurotoxicity. It has been noted that glutamate can be 0107 yö T cells represent a small subset of T cells that toxic to neurons if presented at a high concentration. The term possess a distinct TCR on their surface. A majority of T cells “excitotoxicity' has been used to describe the cytotoxic effect have a TCR composed of two glycoprotein chains called C.- that glutamate (and other such excitatory amino acids) can and B-TCR chains. However, in Yö T cells, the TCR is made have on neurons when applied at high dosages. up of one Y-chain and one Ö-chain. This group of T cells is 0114 Patients with injury or damage of any kind to the much less common (5% of total T cells) than the CfBT cells, central (CNS) or peripheral (PNS) nervous system including US 2010/0210539 A1 Aug. 19, 2010 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: 0119. 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 0.120. Other disorders associated with neuronal injury drome). include, but are not limited to, disorders associated with 0115. 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 0116 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 I0121 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 0117. 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 ders, including but not limited to, progressive, deteriorating or vocal tic disorder, Tourette's disorder, elimination disor forms of bipolar disorder or schizoaffective disorder or ders, encopresis, enuresis, selective mutism, separation anxi Schizophrenia, impulse control disorders, obsessive compul ety disorder, dissociative amnesia, depersonalization disor sive disorder (OCD), behavioral changes in temporal lobe der, dissociative fugue, dissociative identity disorder, epilepsy and personality disorders. anorexia nervosa, bulimia nervosa, bipolar disorders, Schizo 0118. In one preferred embodiment the compounds of the phreniform disorder, schizoaffective disorder, delusional dis invention would be used to provide neuroprotection in disor order, psychotic disorder, shared psychotic disorder, delu ders involving trauma and progressive injury to the nervous sions, hallucinations, Substance-induced psychotic disorder, system in various psychiatric disorders. These disorders orgasmic disorders, sexual pain disorders, dyspareunia, would be selected from the group consisting of Schizoaffec vaginismus, sexual dysfunction, paraphilias, dyssomnias, US 2010/0210539 A1 Aug. 19, 2010 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, 0.126 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 0122) 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 I0127. 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), 0128. 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 0123 Examples for disorders usually first diagnosed in amount of the peptide of the invention to a patient who has not infancy, childhood, or adolescence are: mental retardation, yet developed overt, clinical signs or symptoms of injury or learning disorders, mathematics disorder, reading disorder, damage to the cells of the nervous system but who may be in disorder of written expression, motor skills disorders, devel a high risk group for the development of neuronal damage opmental coordination disorder, communication disorders, because of injury or trauma to the nervous system or because expressive language disorder, phonological disorder, mixed of Some known predisposition either biochemical or genetic receptive-expressive language disorder, Stuttering, pervasive or the finding of a verified biomarker of one or more of these developmental disorders, Asperger's disorder, autistic disor disorders. der, childhood disintegrative disorder, Rett's disorder, perva 0129. 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 0.124 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 0.130. Accordingly, in an exemplary embodiment, subjects related disorders, nicotine related disorders, opioid related who may benefit from treatment by the methods and peptide disorders, psychotic disorder, psychotic disorder, phencycli of this invention can be identified using accepted Screening dine-related disorder, abuse, persisting amnestic disorder, methods to determine risk factors for neuronal damage. These anxiety disorder, persisting dementia, dependence, intoxica screening methods include, for example, conventional work tion, intoxication delirium, mood disorder, psychotic disor ups to determine risk factors including but not limited to: for der, withdrawal, withdrawal delirium, sexual dysfunction, example, head trauma, either closed or penetrating, CNS sleep disorder. infections, bacterial or viral, cerebrovascular disease includ 0.125. The term “neuroprotection” as used herein shall ing but not limited to stroke, brain tumors, brain edema, mean: inhibiting, preventing, ameliorating or reducing the cysticercosis, porphyria, metabolic encephalopathy, drug severity of the dysfunction, degeneration or death of nerve withdrawal including but not limited to sedative-hypnotic or cells, axons or their Supporting cells in the central or periph alcohol withdrawal, abnormal perinatal history including eral nervous system of a mammal, including a human. This anoxia at birth or birth injury of any kind, cerebral palsy, US 2010/0210539 A1 Aug. 19, 2010

learning disabilities, hyperactivity, history of febrile convul embodiments, the present invention provides methods to treat sions as a child, history of status epilepticus, family history of or prevent neuronal injury in a patient. The method includes epilepsy or any seizure related disorder, inflammatory disease the step of administering to a patient in need of treatment, an of the brain including lupis, drug intoxication either director effective amount of one of the peptide disclosed herein in by placental transfer, including but not limited to cocaine combination with an effective amount of one or more other poisoning, parental consanguinity, and treatment with medi compounds or therapeutic agents that have the ability to pro cations that are toxic to the nervous system including psycho vide neuroprotection or to treat or prevent seizures or epilep tropic medications. togenesis or the ability to augment the neuroprotective effects 0131 The determination of which patients may benefit of the compounds of the invention. from treatment with a neuroprotective drug in patients who 0.135. As used herein the term “combination administra have no clinical signs or symptoms may be based on a variety tion of a compound, therapeutic agent or known drug with of “surrogate markers' or “biomarkers’. the peptide of the present invention means administration of 0.132. As used herein, the terms “surrogate marker” and the drug and the one or more compounds at Such time that “biomarker are used interchangeably and refer to any ana both the known drug and the peptide will have a therapeutic tomical, biochemical, structural, electrical, genetic or chemi effect. In some cases this therapeutic effect will be synergis cal indicator or marker that can be reliably correlated with the tic. Such concomitant administration can involve concurrent present existence or future development of neuronal damage. (i.e. at the same time), prior, or Subsequent administration of In some instances, brain-imaging techniques, such as com the drug with respect to the administration of the peptide of puter tomography (CT), magnetic resonance imaging (MRI) the present invention. A person of ordinary skill in the art or positron emission tomography (PET), can be used to deter would have no difficulty determining the appropriate timing, mine whether a Subject is at risk for neuronal damage. Suit sequence and dosages of administration for particular drugs able biomarkers for the methods of this invention include, but and peptides of the present invention. are not limited to: the determination by MRI, CT or other 0.136 The said one or more other compounds or therapeu imaging techniques, of Sclerosis, atrophy or Volume loss in tic agents may be selected from compounds that have one or the hippocampus or overt mesial temporal sclerosis (MTS) or more of the following properties: antioxidant activity; similar relevant anatomical pathology; the detection in the NMDA receptor antagonist activity, augmentation of endog patient's blood, serum or tissues of a molecular species Such enous GABA inhibition: NO synthase inhibitor activity; iron as a protein or other biochemical biomarker, e.g., elevated binding ability, e.g., an iron chelator, calcium binding ability, levels of ciliary neurotrophic factor (CNTF) or elevated e.g., a Ca (II) chelator; Zinc binding ability, e.g., a Zn (II) serum levels of a neuronal degradation product; or other chelator; the ability to effectively block sodium or calcium evidence from Surrogate markers or biomarkers that the ion channels, or to open potassium or chloride ion channels in patient is in need of treatment with a neuroprotective drug. the CNS of a patient. 0133. It is expected that many more such biomarkers uti 0.137 The peptide of the present invention was tested lizing a wide variety of detection techniques will be devel using the assays described in Examples 1-7, 9-17 for their oped in the future. It is intended that any such marker or effect as active therapeutic agents in the prophylaxis and/or indicator of the existence or possible future development of treatment of neurodegenerative diseases and disorders. neuronal damage, as the latter term is used herein, may be used in the methods of this invention for determining the need Heart and Vascular Disease for treatment with the compounds and methods of this inven 0.138 Heart disease is a general term used to describe tion. many different heart conditions. For example, coronary artery 0134. A determination that a subject has, or may be at risk disease, which is the most common heart disease, is charac for developing, neuronal damage would also include, for terized by constriction or narrowing of the arteries Supplying example, a medical evaluation that includes a thorough his the heart with oxygen-rich blood, and can lead to myocardial tory, a physical examination, and a series of relevant bloods infarction, which is the death of a portion of the heart muscle. tests. It can also include an electroencephalogram (EEG), CT, Heart failure is a condition resulting from the inability of the MRI or PET scan. A determination of an increased risk of heart to pump an adequate amount of blood through the body. developing neuronal damage or injury may also be made by Heart failure is not a sudden, abrupt stop of heart activity but, means of genetic testing, including gene expression profiling rather, typically develops slowly over many years, as the heart or proteomic techniques, For psychiatric disorders that may gradually loses its ability to pump blood efficiently. Risk be stabilized or improved by a neuroprotective drug, e.g., factors for heart failure include coronary artery disease, bipolar disorder, schizoaffective disorder, schizophrenia, hypertension, valvular heart disease, cardiomyopathy, dis impulse control disorders, etc. the above tests may also ease of the heart muscle, obesity, diabetes, and/or a family include a present state exam and a detailed history of the history of heart failure. course of the patients symptoms Such as mood disorder Symp 0.139 Examples of cardiovascular diseases and disorders toms and psychotic symptoms over time and in relation to are: aneurysm, stable angina, unstable angina, angina pecto other treatments the patient may have received overtime, e.g., ris, angioneurotic edema, aortic valve Stenosis, aortic aneu a life chart. These and other specialized and routine methods rysm, arrhythmia, arrhythmogenic right ventricular dyspla allow the clinician to select patients in need of therapy using sia, arteriosclerosis, arteriovenous malformations, atrial the methods and formulations of this invention. In some fibrillation, Behcet syndrome, bradycardia, cardiac tampon embodiments of the present invention peptide suitable for use ade, cardiomegaly, congestive cardiomyopathy, hypertrophic in the practice of this invention will be administered either cardiomyopathy, restrictive cardiomyopathy, carotid Steno singly or concomitantly with at least one or more other com sis, cerebral hemorrhage, Churg-Strauss syndrome, diabetes, pounds ortherapeutic agents, e.g., with other neuroprotective Ebstein's Anomaly, Eisenmenger complex, cholesterol drugs or antiepileptic drugs, anticonvulsant drugs. In these embolism, bacterial endocarditis, fibromuscular dysplasia, US 2010/0210539 A1 Aug. 19, 2010 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, 0146 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. 0147 Neuropathy is a general term which describes a 0140 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 0141 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 0.148. 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 014.9 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 0142. One of the more clinically significant forms of PVD like. is peripheral artery disease (PAD). PAD is often treated by 0150. 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 0151. 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, 0143 Peripheral vascular disease is also manifested in health hazard due to vibration, Sudeck's syndrome, intermit atherosclerotic stenosis of the renal artery, which can lead to tent claudication, cold sense in extremities, abnormal sensa renal ischemia and kidney dysfunction. tion in extremities, sensitivity to the cold, Meniere's disease, 0144 One disease in which vascular diseases and their Meniere's syndrome, numbness, lack of sensation, anesthe complications are very common is diabetes mellitus. Diabe sia, resting pain, causalgia (burning pain), disturbance of tes mellitus causes a variety of physiological and anatomical peripheral circulation function, disturbance of nerve func irregularities, the most prominent of which is the inability of tion, disturbance of motor function, motor paralysis, diabetic the body to utilize glucose normally, which results in hyper peripheral circulation disorder, lumbar spinal canal Stenosis, glycemia. Chronic diabetes can lead to complications of the diabetic neuropathy, shock, autoimmune disease Such as vascular system which include atherosclerosis, abnormalities erythematosis, rheumatoid disease and rheumatoid arthritis, involving large and medium size blood vessels (macroangi autonomic neuropathy, diabetic autonomic neuropathy, auto opathy) and abnormalities involving Small blood vessels (mi nomic imbalance, orthostatic hypotension, erectile dysfunc croangiopathy) Such as arterioles and capillaries. tion, female sexual dysfunction, retrograde ejaculation, cys 0145 Patients with diabetes mellitus are at increased risk topathy, neurogenic bladder, defective vaginal lubrication, of developing one or more foot ulcers as a result of established exercise intolerance, cardiac denervation, heat intolerance, US 2010/0210539 A1 Aug. 19, 2010 gustatory Sweating, diabetic complication, hyperglycemia, ostosis, Acrodysplasia, Acrofacial dysostosis, Acrokerato hypoglycemia unawareness, hypoglycemia unresponsive derma, Acrokeratoelastoidosis, Acromelanosis, Acrome ness; glaucoma, neovascular glaucoma, cataract, retinopathy, somelic dwarfism, Acromicric dysplasia, Acroosteolysis diabetic retinopathy, diabetic maculopathy, occlusion of reti dominant type, Acrorenal defect—ectodermal dysplasia— nal artery, obstruction of central artery of retina, occlusion of diabetes, Acrorenal syndrome, Actinic porokeratosis dis retinal vein, macular edema, aged macular degeneration, seminated Superficial, Actinic porokeratosis, Acute Respira aged disciform macular degeneration, cystoid macular tory Distress Syndrome, Acute basophilic leukaemia, Acute edema, palpebral edema, retinal edema, chorioretinopathy, erythroblastic leukaemia, Acute febrile neutrophilic derma neovascular maculopathy, uveitis, iritis, retinal vasculitis, endophthalmitis, panophthalmitis, metastatic ophthalmia, tosis, Acute inflammatory demyelinating polyradiculoneur choroiditis, retinal pigment epithelitis, conjunctivitis, cycli opathy (aidp). Acute interstitial pneumonia, Acute leukaemia tis, Scleritis, episcleritis, optic neuritis, retrobulbar optic neu of ambiguous lineage, Acute leukaemia of indeterminate lin ritis, keratitis, blepharitis, exudative retinal detachment, cor eage, Acute liver failure, Acute lymphoblastic leukaemia, neal ulcer, conjunctival ulcer, chronic nummular keratitis, Acute medullary lesions, Acute megacaryoblastic leukaemia, Thygeson keratitis, progressive Mooren's ulcer, damage of Acute monoblastic leukaemia, Acute motor and sensory skin, skin ulcer including foot ulcer, diabetic ulcer, burn ulcer, axonal neuropathy (AMSAN), Acute motor axonal neuropa lower leg ulcer, postoperative ulcer, traumatic ulcer, ulcer thy (AMAN), Acute myeloblastic leukaemia, Acute myelod after herpes Zoster, radiation ulcer, drug induced ulcer, frost ysplasia with myelofibrosis, Acute myelofibrosis, Acute bite (cold injury), chilblain, gangrene and Sudden gangrene, myeloid leukaemia in Down syndrome, Acute myelomono angina pectoris/variant angiitis, coronary arteriosclerosis cytic leukaemia, Acute myelosclerosis, Acute non lympho (chronic ischemic heart disease, asymptomatic ischemic blastic leukaemia, Acute panmyelosis with myelofibrosis, heart disease, arteriosclerotic cardiovascular disease), myo Acute peripheral arterial occlusion, Acute promyelocytic leu cardial infarction, heart failure, congestive heart failure and kaemia, Acute tubulointerstitial nephritis and uveitis Syn painless ischemic heart disease, pulmonary edema, hyperten drome, Adactylia unilateral, Adamantinoma, Adams nance Sion, pulmonary hypertension; portal hypertension, diabetic syndrome, Adams-Oliver syndrome. Addison's disease, Adenine phosphoribosyltransferase deficiency, Adenosine nephropathy, decubitus, renal failure. deaminase deficiency, Adenosylcobalamin deficiency, Aden 0152 The peptide of the present invention was tested ovirus infection in immunocompromised patients, Adenylo using the assays described in Examples 1-7, 9-17 for their Succinase deficiency Adhesive arachnoiditis, Adie syndrome, effect as active therapeutic agents in the prophylaxis and/or Adrenal adenoma, Adrenal hyperplasia, Adrenal incidenta treatment of heart and vascular diseases and disorders. loma, Adrenal insufficiency, Adrenocortical carcinoma, Adrenoleukodystrophy, Adrenomyeloneuropathy, Rare or Orphan Diseases Adrenomyodystrophy, Adult Onset Still's disease, Adult 0153. Another aspect of the present invention is directed to T-cell leukaemia/lymphoma, Adult idiopathic neutropenia, the use of the peptide as a therapeutic agent for the prophy Adult neuronal ceroid lipofuscinosis (Kufs disease, CLN4), laxis and/or treatment of a heart and vascular disease, an Adult spinal muscularatrophy, Afibrinogenemia, African tick autoimmune disease, a fibrotic disease, an inflammatory dis typhus, African trypanosomiasis, Agammaglobulinemia, ease, a neurodegenerative disease, oran infectious disease, in Age-related macular degeneration, Ahn-Lerman-Sagie Syn patients suffering from one or more of the following Rare or drome, Ahumada-Del Castillo syndrome, Aicardi syndrome, Orphan Diseases: Aicardi-Goutieres syndrome, AIDS, Akaba hayasaka Syn 0154 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, AHDS, 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, Amegac pulmonary artery, Abetalipoproteinemia, Ablepharon mac aryocytosis, Amelia, Aminoaciduria, Amoebiasis due to rostomia syndrome, Abruzzo-Erickson syndrome, Acalvaria, Entamoeba histolytica, Ampola syndrome, Amyloid cardi Acampomelic campomelic dysplasia, Acanthamoeba kerati opathy, Amyloid nephropathy, Amyloid polyneuropathy, tis, Acanthocytic disorder, Acanthocytosis, Acanthosis nigri Amyloidosis, Amylopectinosis, Amyoplasia congenita, cans, Acatalasemia, Aceruloplasminemia, Achalasia, Achard Amyotrophic lateral Sclerosis, Amyotrophy fat tissue Thiers syndrome, Ad Acheiropodia, Achondroplasia, Achro anomaly, Anemia, Anauxetic dysplasia, Ancylostomiasis, matopsia, Acitretin embryofetopathy, Ackerman syndrome, Andermann syndrome, Andersen disease, Aneurysmal Sub Acoustic neurinoma, Acquired generalized lipodystrophy, arachnoid haemorrhage, Angelman syndrome, Angio-osteo Acquired hypoprothrombinemia, Acquired ichthyosis, hypertrophic syndrome, Angiodysgenetic necrotizing myel Acquired idiopathic sideroblastic anaemia, Acquired opathy, 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 US 2010/0210539 A1 Aug. 19, 2010 oedema, Angiostrongyliasis, Anguillulosis, Aniridia, Rimoldi syndrome, Benallegue Lacete syndrome, Beel, Anisakiasis, Ankylosing spondylarthritis, Ankylostomiasis, Bencze syndrome, Bennion-Patterson syndrome, Benson's Annuloaortic ectasia, Anodontia, Anonychia, Anoph syndrome, Beradinelli-Seip syndrome, Berdon syndrome, thalmia heart and pulmonary anomalies. Anorchidia, Anor Berger disease, Berk tabatznik syndrome, Berlin breakage exia nervosa, Anotia, Antenatal Epstein-Barr virus infection, syndrome, Bernard-soulier syndrome, Berylliosis, Besnier Anterior horn cell disease, Anti-phospholipid syndrome, Boeck-Schaumann disease, Bessel-Hagen disease, Best dis Antinolo nieto borrego Syndrome, Antiplasmin deficiency, ease, Beta thalassemia, Bethlem myopathy, Bickel-Fanconi Antithrombin deficiency, Antley-Bixler syndrome. Anyane glycogenosis, Bickers-Adams syndrome, Bickerstaffs brain Yeboa syndrome, Aorta coarctation, Aorta hypoplasia, Aorta stem encephalitis, Bicuspidaortic valve, Biemond syndrome, pulmonary artery fistula, Aortic aneurysm syndrome, due to Biermer disease, Bietti's crystalline dystrophy, Bile acid syn TGFbeta receptors anomalies, Aortic malformation, Aortic thesis defect, Bile duct cancer, Biliary atresia, Biliary inflam valve atresia, Aortic valve dysplasia, Aortic valve Stenosis, matory disease, Bilineal acute leukaemia, Billard-Toutain APECED syndrome, Apert syndrome, Aphasia, Apical bal Maheut syndrome, Binder syndrome, Bindewald-Ulmer looning syndrome, Aplasia cutis, Aplastic anaemia, Apnea of Muller syndrome, Binswanger disease, Birt–Hogg–Dube infancy (AIO), Apnea of prematurity (AOP), Apo A-I defi syndrome, Bixler christian gorlin syndrome, Bjornstad Syn ciency, Apollipoprotein AI amyloidosis, Apple peel Syn drome, Blackfan-Diamond anaemia, Blaichman syndrome, drome, Apraxia, Arbovirus fever, Arena syndrome, Areolar Blake's pouch cyst, Blau syndrome, Blepharophimosis, Ble atrophy of the macula, Argyria, Argyrophilic grain disease, pharoptosis, Blepharospasm, Blethen wenick hawkins Syn Arhinia choanal atresia microphthalmia, Arkless-Graham drome, Bloch-Sulzberger syndrome, Bloom syndrome, syndrome, Armfield syndrome, Arndt-Gottron disease, Blount disease, Blue Diaper syndrome, Bohring syndrome, Arnold-Chiari malformation, Aromatase deficiency, Bohring-Opitz syndrome, Boichis syndrome, Bone disease Arrhinia, Arrhythmogenic right ventricular dysplasia, Arte with defective bone mineralisation, Bone disease with rial calcification, Arterial duct anomalies, Arterial occlusive increased bone density, Bone marrow failure, Bonneau 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—fallot tetralogy, Atrophia aerata, Atro tyly arterial hypertension, Brachymesophalangy II and V. phoderma Vermiculata, Atypical Mole syndrome, Atypical Brachyolrnia, 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 US 2010/0210539 A1 Aug. 19, 2010 ming type, Camptodactyl), Camurati engelmann disease, Congenital lobar emphysema, Conjunctival disease, Con Canale-Smith syndrome, Canavan disease, Candidiasis, Can junctival vascular anomaly, Conn syndrome, Connective tis talamessa baldini ambrosi Syndrome, Canthus, Carbohydrate Sue disease, Conradi-Hunermann-Happle syndrome, Con metabolism disorder, Cardiogenital syndrome, Cardiomy strictive bronchiolitis, Cooks syndrome, Cooley anaemia, opathy, Cardioskeletal myopathy, Carey fineman Ziter Syn Cooper-Jabs Syndrome, Cormier rustin munnich syndrome, drome, Carnevale canun mendoza syndrome, Carnevale-Her Corneal dystrophy, Cornelia de Lange syndrome, Corneoder nandez-del Castillo syndrome, Carnevale-Krajewska matoosseous syndrome, Corneogoniodysgenesis, Coronaro Fischetto syndrome, Carney complex, Carney-Stratakis cardiac fistula, Coronary arterial malformations, Coronary syndrome, Carnosinase deficiency, Carnosinemia, Caroli's artery aneurysm, Coronary sinus type ASD, Cortada koussef disease, Carpal Tunnel syndrome, Carpenter syndrome, Car matsumoto syndrome, Costeffoptic atrophy syndrome, Cost penter-Waziri syndrome, Carrington's disease, Carrion dis eff syndrome, Costello syndrome, Cotekatsantoni syndrome, ease, Carvajal syndrome, Casamassima-Morton-Nance Syn Cousin-Walbraum-Cegarra syndrome, Cowchock syndrome, drome, Cassia Stocco dos Santos syndrome, Castleman Cowchock-Wapner-Kurtz syndrome, Cowden syndrome, disease, Castro gago pombo novo syndrome, Catalase defi Coxoauricular syndrome, Cramer-Niederdellmann Syn ciency, Cataract, Catel-Manzke syndrome, Cayler syndrome, drome, Crandall syndrome, Crane heise syndrome, Cranial Celiac disease, Celosomia, Cenani lenZ Syndactylism, Cen malformation, Craniopharyngioma, Craniorachischisis, tral neurocytoma, Cephalopolysyndactyl), Ceramidase defi Craniostenosis, Craniosynostosis, Craniotelencephalic dys ciency, Cerebellar hypoplasia, Cerebral arteriovenous shunt, plasia, Craniotubular syndrome, Creatine deficiency, Creep Cerebral hemorrhage with amyloidosis, Cerebroretinal vas ing disease, Creutzfeldt-Jakob disease, Cri du chat syndrome, culopathy, Cfc syndrome, Chagas disease, Chanarin disease, Crigler-Najjar syndrome, Crimean-Congo haemorragic fever Chandler syndrome, Chang-Davidson-Carlson syndrome, (CCHF), Crisponi syndrome, Criss-cross heart, Criswick Chaotic atrial tachycardia, Char douglas dungan syndrome, Schepens syndrome, Crohn disease, Crome syndrome, Char syndrome, Charge syndrome, Charlevoix disease, Char Cronkhite canada syndrome, Cross syndrome, Crouzon dis lie m syndrome, Chediak-Higashi like syndrome, Cheilitis ease, Crow-Fukase syndrome, Cryoglobulinaemia mixed, glandularis, Chemke oliver mallek syndrome, Chemodec Cryptococcosis, Cryptogenic organizing pneumonia, Cryp toma, Chemy-red-spot myoclonus syndrome, Cherubism, tophthalmia, Cryptosporidiosis, Culler-Jones syndrome, Chiari Frommel syndrome, Chitayat hajchahine syndrome, Currarino triad, Curry-Hall syndrome, Curry-Jones syn Chitayat moore del bigio syndrome, Chitayat-Meunier drome, Cushing disease, Cutaneomeningospinal angiomato Hodgkinson syndrome, Chitty hall Webb syndrome, Chitty sis, Cutaneous lupus erythematosus, Cutaneous mastocy Hall-Baraitser syndrome, Cholera, Cholestasis, Cholesteryl toma, Cutaneous mastocytosis, Cutaneous photosensitivity ester storage disease, Choline atetyltransferase (Ch.AT) defi colitis, Cutaneous vasculitis, Cutaneuous myiasis, Cutis laxa, ciency, Chondrocalcinosis, Chondrodysplasia, Chondrodys Cutler bass rom she syndrome, Cyclosporosis, CyStathioni trophy, Chordoma, Choreoacanthocytosis, Chorioretinal nuria, Cystic fibrosis, Cystic hamartoma of lung and kidney, atrophy, Choristoma, Choroidal dystrophy, Choroidal sclero Cystic lymphangioma, Cystic renal disease, Cystinosis, sis, Choroideremia, Christ-Siemens-Touraine syndrome, Cystinuria, Cytochrome c oxydase deficiency, Cytomega Christian syndrome, Christian-Rosenberg syndrome, Chris lovirus (CMV) disease in patients with impaired cell medi tianson syndrome, Christianson-Fourle syndrome, Christmas ated immunity deemed at risk, Cytopenia, Czeizel brooser tree syndrome, Chronomycosis, Chronic eosinophilic pneu syndrome, Czeizel losonci syndrome, Dercole syndrome, monia, Chronic fatigue syndrome, Chronic inflammatory D-2-hydroxyglutaricaciduria, D-glycerate dehydrogenase demyelinating polyneuropathy, Chronic myeloproliferative deficiency (hyperoxaluria type 2), D-glycerate kinase defi disease, Chronic neutrophilic leukaemia, Chronic pain ciency, D-glycericacidemia, DCMA syndrome, DCMD, requiring intraspinal analgesia, Chronic pneumonitis of DEND syndrome, DI-CMT, DIDMOAD syndrome (Diabe infancy, Chronic osteomyelitis, Chronic spinal muscular tes Insipidus—Diabetes Mellitus Optic Atrophy—Deaf atrophy, Chudley rozdilsky syndrome, Chudley-Lowry-Hoar ness), DIS, DK phocomelia syndrome, DKC, DOOR syn syndrome, Churg-Strauss syndrome, Chylomicron retention drome, DORV, DTDP1, DYT6, Da silva syndrome, disease, Ciliary dysentery, Ciliary dyskinesia-bronchiectasis, Dacryocystitis osteopoikilosis, Daentl-Townsend-Siegel Cilliers-Beighton syndrome, Cirrhosis associated cardiac syndrome, Dahlberg-Borer-Newcomer syndrome, Daish dysfunction, Cirrhotic cardiomyopathy, Clarkson disease, hardman lamont syndrome, Dancing Eye syndrome, Dandy Classical Hodgkin disease, Classical homocystinuria, walker malformation, Daneman davy mancer syndrome, Claude-Bernard-Horner syndrome, ClaytonSmith-Donnai Danon disease, Darier disease, Darier-Gottron disease, Dav syndrome, Cleido rhizomelic syndrome, Cleidocranial dys enport donlan syndrome, David Syndrome, Davies disease, ostosis, Cleidocranial dysplasia, Clouston syndrome, Coagu Davis lafer syndrome, De Barsy syndrome, De Hauwere lation disorder, Coarctation of aorta, Coats disease, Cobb Leroy-Adriaenssens syndrome, De Santis-Cacchione syn syndrome, Cocaine poisoning, Cockayne syndrome, Codas drome, De Smet-Fabry-Fryns syndrome, De Vaal disease, De syndrome, Coeliac disease, Coenzyme cytochrome c reduc la Chapelle dysplasia, De morsier syndrome, Deafness— tase deficiency, Coffin syndrome, Coffin-Lowry syndrome, small bowel diverticulosis—neuropathy, Deal barratt dillon Coffin-Siris syndrome, Cogan syndrome, Cogan-reese syn syndrome, Degos disease, Dejerine-Sottas Syndrome, Deka drome, Cohen hayden syndrome, Cohen lockood Wyborney ban-Arima syndrome, Delayed graft function after organ syndrome, Cohen syndrome, Cole carpenter syndrome, Coli transplantation, Delleman-Oorthuys syndrome, Dementia tis, Collagen anomaly, Collins pope syndrome, Collins Sakati associated with a metabolic disease, Dementia associated syndrome, Coloboma, Colon cancer, Colonic atresia, Colo with a neurodegenerative disease, Dementia associated with rado tickencephalitis, Combined pituitary hormone deficien an infectious disease, Dementia associated with hepatic and cies, Complement component deficiency, Congenital Lam renal failure, Demodicidosis, Dendritic cell sarcoma, Den bert-Eaton-like syndrome, Congenital leptin deficiency, dritic cell tumor, Dengue, Dennis cohen syndrome, Dennis US 2010/0210539 A1 Aug. 19, 2010 fairhurst moore syndrome, Dense (delta) granule disease, carcinoma, Esophageal atresia, Essential cryoglobulinaemia, Dent disease, Dentin dysplasia, Denys-Drash syndrome, Der Essential iris atrophy, Essential osteolysis, Esthesioneuro Kaloustian-Jarudi-Khoury syndrome, Der kaloustian mcin blastoma, Estrogen receptor deficiency, Estrogen resistance tosh silver syndrome, Dercum’s disease, Dermatofibrosar syndrome, Evans syndrome, Ewing sarcoma, Exner Syn coma protuberans, Dermatologic allergic disease, Derma drome, Exostoses, EXSudative retinopathy, Extracutaneous tostomatitis Stevens Johnson type, Desbuquois syndrome, mastocytoma, Extrinsic allergic alveolitis, Eye disease, F Desminopathy, Desmoid disease, Desmosterolosis, Devic's syndrome, FAP, FAS deficiency, FCS syndrome, FCU, disease, DeVriendt legius fryns syndrome, DeVriendt vanden FENIB, FEOM, FFDD type I, FG syndrome, FLOTCH syn berghe fryns Syndrome, DiGeorge syndrome, Diabetes, drome, FOP, FOSMN syndrome, FPS/AML syndrome, Dialysis-related arthropathy, Diaphanospondylodysostosis, FRAXA syndrome, FRAXE syndrome, FRAXF syndrome, Diaphragmatic agenesia, Diaphragmatic spinal muscular FSH resistance, Fabry disease, Factor VII deficiency, Factor atrophy, Diffuse alveolar haemorrhage, Diffuse large B cell VIII deficiency, Factor X deficiency, Factor XI deficiency, lymphoma, Diffuse leiomyomatosis—Alport syndrome Factor XII deficiency, Factor XIII deficiency, Factors II, VII, X-linked. Diffuse neonatal haemangiomatosis, Dihydropyri IX and X, combined deficiency, Fahr syndrome, Fallot com midlinuria, Dilated cardiomyopathy with ataxia, DincSoy-Sa plex, Familial LCAT deficiency, Fanconi anaemia, Fanconi lih-Patel syndrome, Dinno shearerweisskopf syndrome, Dio ichthyosis dysmorphism, Fanconi syndrome, Fanconi-Bickel medi bernardi placidi syndrome, Dionisi-Vici-Sabetta disease, Fara-Chlupackova Syndrome, Farber lipogranulo Gambarara syndrome, Diphtheria, Diprosopia, Discoid lupus matosis, Farmer's lung disease, Fatal infantile COX defi erythematosus, Discrete fibromuscular Subaortic Stenosis, ciency, Faulk-Epstein-Jones syndrome, Favism, Fazio-Londe Distichiasis—congenital heart defects peripheral vascular disease, Fechtner syndrome, Feigenbaum-Bergeron-Rich anomalies, Distomatosis, Dobrow syndrome, Donath-Land ardson syndrome, Feingold syndrome, Felty syndrome, Fen Steiner syndrome, Donnai-Barrow syndrome, Donohue Syn ton Wilkinson toselano syndrome, Ferlini-Ragno-Calzolari drome, Doose syndrome, Dorfman-chanarin disease, Dowl syndrome, Fernhoff-Blackston-Oakley syndrome, Fetal ing-Degos disease, Dowling-Degos-Kitamura disease, Down cytomegalovirus syndrome, Fetal edema, Fetal left ventricu syndrome, Doyne honeycomb retinal dystrophy (DHRD), lar aneurysm, Fibrinogen disorder, Fibrochondrogenesis, Drachtman Weinblatt SitarZ Syndrome, Drash syndrome, Fibrodysplasia ossificans progressiva, Fibromatosis, Fibro Dravet syndrome, Drummond syndrome, Du Pan syndrome, muscular dysplasia of arteries, Fibromyalgia, Fibronectin Duane syndrome, Dubin-Johnson syndrome, Dubowitz Syn glomerulopathy, Fibrosarcoma, Fibrosing mediastinitis, drome, Duhring brocq disease, Duker-Weiss-Siber syn Fibrosis of extraocular muscles, Fiessinger-Leroy-Reiter's drome, Dunnigan syndrome, Dupont sellier chochillon Syn syndrome, Figuera syndrome, Filamin anomaly, Filariasis, drome, Dyggve-Melchior-Clausen disease, Dykes-Markes Filippi syndrome, Fine-Lubinsky syndrome, Finlay-Markes Harper syndrome, Dyschondrosteosis, Dyschromatosis syndrome, Finucane kurtz, Scott syndrome, Fitz Hugh Curtis universalis, Dysferlinopathy, Dysfibrinogenemia, Dyskera syndrome, Fitzsimmons-Guilbert syndrome, Fitzsimmons tosis, Dysmorphic syndrome with connective tissue involve McLachlan-Gilbert syndrome, Fitzsimmons-Walson-Mellor ment, Dysosteosclerosis, Dysostosis, Dysphagia lusoria, syndrome, Fixed Subaortic Stenosis, Flegel disease, Floating Dysplasia, Dysprothrombinemia, Dyssegmental dysplasia Harbor syndrome, Florid cemento-Osseous dysplasia, Flynn glaucoma, Dysspondyloenchondromatosis, Dystoni-like aird syndrome, Foix chavany marie Syndrome, Foix-Alajoua syndrome with paroxysmal disease, Dystonia, EBD, EBJ, nine syndrome. Follicular atrophoderma-basal cell carci EBS, ECP syndrome, EDS III, EEC syndrome, EEM syn noma, Follicular dendritic cell sarcoma, Follicular dys drome, EGE, ENT, ERA, ESS1, Eagle-Barret syndrome, keratoma, Follicular ichthyosis, Follicular lymphoma, Eales disease, Ebola virus disease, Echinocytic disorder, Fontaine-Farriaux-Blanckaert syndrome. Forbes disease, Ectodermal dysplasia, Ectromelia, Ectropion, Eczema Formey-Robinson-Pascoe syndrome, Forunculoid myiasis, thrombocytopenia-immunodeficiency syndrome, Edinburgh Fountain syndrome, Fowler-Christmas-Chapple syndrome, malformation syndrome, Edward syndrome, Edwards-Pat Fox Fordyce disease, Fra-X syndrome, Fragile X syndrome, ton-Dilly syndrome, Ehlers-Danlos syndrome, Ehrlichiosis, Fragoso cidgarcia hernandez syndrome, Franceschetti-Klein Eiken syndrome, Eisenmenger syndrome, Elastosis per syndrome, Francois dyscephalic syndrome, Francois Syn forans serpiginosa, Elejalde syndrome, Elliott ludman teebi drome, Franekbocker kahlen syndrome, Frank-Ter Haar syn syndrome, Elliptocytosis, Ellis Van Creveld syndrome, Ellis drome, Franklin disease, Fraser like syndrome, Fraser Syn yale winter syndrome, Elsching syndrome, Emanuel Syn drome, Frasier syndrome, Freeman-Sheldon syndrome, drome, Emery-Dreifuss muscular dystrophy, Emery-Nelson Freiberg's disease, Freire mala pinheiro opitz syndrome, syndrome, Empty Sella syndrome, Encephalitis, Encephalo Frey's syndrome, Frias syndrome, Fried syndrome, Fried myelitis, Encephalopathy, Enchondromatosis, Endometrio Goldberg-Mundel Syndrome, Friedman goodman syndrome, sis, Endotheliitis, Eng Strom Syndrome, Engel congenital Friedreich ataxia, Froelich's syndrome. Froster-Huch syn myasthenia, Engelhardyatziv Syndrome, Enolase deficiency, drome. Froster-Iskenius-Waterson syndrome, Fructosuria, Enteric anendocrinosis, Enteropathy, Enterovirus antenatal Frydman-Cohen-Karmon syndrome, Fryns macrocephaly, infection, Entropion, Envenomization, Eosinophilic Fryns-Aftimos syndrome, Fryns-Hofkens-Fabry syndrome, endocarditis, Eosinophilic pneumonia, Ependymoma, Epi Fuhrmann-Rieger-de Sousa syndrome, Fukuda miyanomae dermolysis bullosa, Epilepsy, Epiphyseal dysplasia, Episodic nakata syndrome, Fukuhara syndrome, Fuqua-Berkovitz Syn ataxia, Epispadias, Epithelial ovarian cancer, Epithelioma, drome. Furlong syndrome, Furukawa takagi nakao Syn Epstein-Barr virus infection, Erdheim disease, Erdheim drome, G syndrome, G6PD deficiency, GABA metabolism Chester disease, Eronen-Somer-Gustafsson syndrome, disease, GAMT deficiency, GAPO syndrome, GIST, GM1 Erythema, Erythermalgia, Erythroblastopenia, Erythrocyto gangliosidosis, GOSHS, GRACILE syndrome, GRF sis, Erythroderma, Erythrokeratoderma, Erythromelalgia, Tumour, GSD, GTN, GVH, Gaisbock syndrome, Galactoki Escher hirt syndrome, Escobar syndrome, Esophageal adeno nase deficiency, Galactosemia, Galactosialidosis, Galloway US 2010/0210539 A1 Aug. 19, 2010

syndrome, Galloway-Mowat Syndrome, Gamborg nielsen streiff like syndrome, Hallermann-Streiff-Francois syn syndrome, Game-Friedman-Paradice syndrome, Gamstorp drome, Hallervorden-Spatz disease, Hamanishi ueba tsuji episodic adynamy, Ganglioglioma, Garcia torres guarner syndrome, Hamano tsukamoto syndrome, Hamman-Rich syndrome, Garcia-Lurie Syndrome, Gardner silengo wachtel syndrome, Hanhart syndrome, Hand Foot Mouth syndrome, syndrome, Gardner-Morrison-Abbott syndrome, Garret tripp Hand-Shuller-Christian disease, Hanot syndrome, Hantavi syndrome, Gastric cancer, Gastroschisis, Gaucher disease, rus pulmonary syndrome, Hapnes boman skele syndrome, Gaucher-like disease, Geen Sandford davison syndrome, Happy puppet syndrome, Harboyan syndrome, Hardcastle Gelineau disease, Gemignani syndrome, Gemss syndrome, syndrome, Harding ataxia, Harrod syndrome, Harrod-Keele Genes syndrome, Genochondromatosis, Gerbode defect, syndrome, Hartnup disorder, Hartsfield bixler demyer syn Gerhardt syndrome, German syndrome, Gershonibaruch drome, Hashimoto struma, Hashimoto-Pritzker syndrome, Leibo syndrome, Gerstmann-Straussler-Scheinker Syn Haspeslagh-Fryns-Muelenaere syndrome, Hawkinsinuria, drome, Ghosal syndrome, Gianotti Crosti Syndrome, Giant Hay wells syndrome, Heart block progressive, Heart-hand cell arteritis, Giant platelet syndrome, Gilbert syndrome, syndrome, Heavy chain deposition disease, Hec Syndrome, Gilles de la Tourette syndrome, Gillespie syndrome, Gitel Hecht scott syndrome, Heckenlively syndrome, Heide syn man syndrome, Glanzmann thrombasthenia, Glass bone dis drome, Heimler syndrome, Heiner syndrome (cow’s milk ease, Glass-Chapman-Hockley Syndrome, Glaucoma, Glio hypersensitivity), Helmerhorst heaton crossen syndrome, blastoma, Glomerular disease, Glomerulonephritis, Hemangioma-thrombocytopenia syndrome, Hemangioperi Glomerulopathy with fibronectin deposits (GFND), Gloomy cytoma, Hematopoietic hypoplasia, Hemeralopia, Hemi, 3 syndrome, Glucagonoma, Glucocorticoid resistance, Glyco syndrome, Hemiconvulsion-Hemiplegia-Epilepsy Syn gen storage disease, Gms syndrome, Goiter-deafness Syn drome, Hemifacial hyperplasia Strabismus, Hemihypertro drome, Golabi-Rosen syndrome, Goldberg syndrome, Gold phy intestinal web cornealopacity, Hemimelia, Hemitruncus, berg-Maxwell syndrome, Goldberg-Shprintzen megacolon Hemochromatosis, Hemoglobin C disease, Hemoglobin E syndrome, Goldblatt viljoen syndrome, Goldblatt wallis syn disease, Hemoglobin H disease, Hemolytic anaemia, Hemo drome, Goldenhar syndrome, Goldmann-Favre syndrome, philia, Hemorrhagiparous thrombocytic dystrophy, Hen Goldstein hutt syndrome, Goldston syndrome, Gollop Syn nekam koss de geest syndrome, Hennekam syndrome, Hen drome, Gollop wolfgang complex, Goltz syndrome, Goltz nekam-Beemer syndrome, Henoch-Schoenlein purpura, Gorlin syndrome, Combo syndrome, Gonzales del angel Syn Hepatic cystic hamartoma, Hepatic fibrosis, Hepatic cancer, drome, Goodman syndrome, Goodpasture syndrome, Hepatic venoocclusive disease, Hepatitis B re-infection fol Goossens-Devriendt syndrome, Gordon syndrom, Gorham lowing liver transplantation, Hepatitis, Hepatoblastoma, syndrome, Gorham-Stout disease, Gorlin syndrome, Gorlin Hepatocellular adenoma, Hepatocellular carcinoma, Hepato Chaudhry-Moss syndrome, Graft rejection after lung trans erythropoeitic porphyria, Hepatoportal sclerosis, Hereditary plantation, Graft versus host disease, Graham boyle troxell coproporphyria, Hereditary endotheliopathy—retinopathy— syndrome, Graham-Cox syndrome, Grand-Kaine-Fulling nephropathy—stroke, Hereditary lymphoedema type I. syndrome, Grange occlusive arterial syndrome, Grant Syn Hereditary motor and sensory neuropathy, Hereditary vascu drome, Granulocytic sarcoma, Granulomatous allergic angii lar retinopathie Raynaud phenomenon—migraine, Her tis, Granulomatous inflammatory arthritis, dermatitis, and mansky-Pudlak syndrome, Hernandez fragoso syndrome, uveitis, Granulomatous mastitis, Graves disease, Gray plate Hernandez-Aguirre Negrete syndrome, Herpes virus infec let syndrome, Greenberg dysplasia, Greig syndrome, Grei tion, Herrmann opitz arthrogryposis syndrome, Hers disease, ther's disease, Griscelli disease, Grix blankenship peterson Hersh-Podruch-Weisskopf syndrome, Herva disease, Hetero syndrome, Groll hirschowitz syndrome, Gronblad-Strand taxia, Heterozygous OSMED, Hillig syndrome, Hinman syn berg-Touraine syndrome, Grosse syndrome, Grover's dis drome, Hinson-Pepys disease, Hipo syndrome, Hirayama ease, Growth hormone deficiency, Grubben de cock borgh disease, Hirschsprung disease, Hirsutism, His bundle tachy graef syndrome, Gräsbeck-Imerslund disease, Guam disease, cardia, Histidine metabolism disorder, Histidinuria renal Guanidinoacetate methyltransferase deficiency, Guibaud tubular defect, Histiocytic and dendritic cell tumour. Histio Vainsel syndrome, Guillain-Barré syndrome, Guizar cytic sarcoma, Histiocytoid cardiomyopathy. Histiocytosis Vasquez-Luengas syndrome, GuizarVazquez-Sanchez-Man X, Histoplasmosis, Hittner hirschkreh syndrome, Hmc syn Zano syndrome, Gunal seber basaran syndrome, Gurrieri drome, Hodgkin lymphoma, Hoepffner dreyer reimers Syn Sammito-Bellussi syndrome, Gusher syndrome, drome, Hoffman's syndrome, Holmes benacerraf syndrome, Gynandroblastoma, Günther disease, HAD deficiency, HAE, Holmes collins syndrome, Holmes-Gang syndrome, Holoac HAIRAN syndrome, HANAC syndrome, HARD syndrome ardius amorphus, Holoprosencephaly, Holt-Oram syndrome, (Hydrocephalus—agyria—retinal dysplasia), HCDD, HCL, Holzgreve Wagner rehder syndrome, Homocarnosinosis, HDL metabolism disorder, HEM, HEP, HERNS syndrome, Homocystinuria, Homogentisic acid oxydase deficiency, HHE syndrome, MHT, HHV-8, HID syndrome, HIGM1, Hoon hall syndrome, Horner syndrome, Horton disease, HIT, HMSN 5, HMSNP, HNPCC, HNSCC, HPA-1 defi Houlston ironton temple syndrome, House allergicalveolitis, ciency, HPE, HSAN 1, HSD deficiency, HSV encephalitis, Howard young syndrome. Howell-Evans syndrome, Hoyer HSV keratitis, HUS, HVR, Haas-Robinson syndrome, Had aal-Hreidarsson syndrome, Humeroradial Synostosis, dad Syndrome, Haematologic cancers, Haemochromatosis, Humeroradioulnar Synostosis, HumeroSpinal dysostosis, Haemoglobin disorders, Haemolysis, Haemolytic anaemia, Hunter carpenter mc donald Syndrome, Hunter jurenka Haemolytic uremic syndrome, Haemorrhagic fever, Haemor thompson syndrome, Hunter syndrome, Hunter-Rudd-Hoff rhagiparous thrombocytic dystrophy, Hageman factor defi mann syndrome, Hunter-Thompson-Reed syndrome, Hun ciency, Hagemoser weinstein breSnick syndrome, Hailey tington disease, HurieZ Syndrome, Hurler syndrome, Hurler Hailey disease, Haim-Munk syndrome, Hairy cell leukaemia, Scheie syndrome, Hutchinson-Gilford syndrome, Hutteroth Hajdu-Cheney syndrome, Hal-Berg-Rudolph syndrome, spranger syndrome, Hyaline membrane disease, Hyalu Halal syndrome, Halal-Setton-Wang syndrome, Hallermam ronidase deficiency, Hydatidosis, Hyde-Forster-Mccarthy US 2010/0210539 A1 Aug. 19, 2010 20

Berry syndrome, Hygroma cysticum, Hyperaldosteronism, syndrome, Jeune syndrome, Job syndrome, Johanson-Bliz Hyperargininemia, Hyperbilirubinemia, Hypercalciuria idio Zard syndrome, Johnson syndrome, Johnson-McMillin Syn pathic, Hypercholesterolemia, Hyperchylomicronemia, drome, Johnson-Munson syndrome, Johnston-Aarons-Schel Hypercortisolism, Hyperexplexia, Hyperglycinemia, Hyper ley Syndrome, Jones syndrome, Jorgenson lenz, syndrome, imidodipeptiduria, Hyperinsulinism, Hyperkeratosis, Hyper Joubert syndrome, Joubert-Boltshauser syndrome, Juberg lipidaemia, Hyperlipoproteinemia, Hyperlysinemia, Hyper hayward syndrome, Juberg-Marsidi syndrome, Judge misch methioninemia, Hyperornithinemia, Hyperostosis, Wright syndrome, Jumping Frenchman of Maine, Jung Wolff Hyperoxaluria, Hyperparathyroidism, Hyperphalangism back Stahl syndrome, Juvenile chronic myelomonocytic leu dysmorphy bronchomalacia, Hyperphenylalaninemic kaemia, Juvenile gastrointestinal polyposis, Juvenile glau embryopathy, Hyperpipecolatemia, Hypersensitivity pneu coma, Juvenile hemochromatosis, Juvenile hyaline fibroma monitis, Hypertelorism, Hyperthermia, Hyperthyroidism, tosis, Juvenile idiopathic arthritis, Juvenile macular Hypertrichosis, Hypertrophic neuropathy, Hypertrophic or degeneration, Juvenile myelomonocytic leukaemia, Juvenile Verrucous lupus erythematosus, Hypertrophic Subaortic polyposis syndrome (JPS), Juvenile temporal arteritis, KBG Stenosis, Hypobetalipoproteinemia, Hypobetalipoproteine syndrome. KBG-like syndrome, KID syndrome, Kabuki syn mia, Hypochondroplasia, Hypocomplementaemic leucocy drome, Kaeser syndrome, Kahler's disease, Kaler garrity toclasic vasculitis, Hypodontia, Hypofibrinogenemia, Stern syndrome, Kallin syndrome, Kallmann syndrome, Hypokalemic alkalosis, Hypokeratosis, Hypomyelination, Kalyanaraman syndrome, Kanzaki disease, Kaplan-Plauchu Hypoparathyroidism, Hypopituitarism, Hypoplastic left Fitch syndrome, Kaplowitz-Bodurtha syndrome, Kaposi's heart syndrome, Hypoplastic right heart syndrome, Hypos sarcoma, Kaposiform hemangioendothelioma, Kapur-Tori padias, Hypothalamic hamartoblastoma syndrome, Hypothy ello syndrome, Karandikar-Maria-Kamble syndrome, Kar roidism, Hypotrichosis, Hypoxanthine guanine phosphoribo sch neugebauer syndrome, Kartagener syndrome, Kasabach syltransferase (HPRT) complete deficiency, 1-cell disease, Merritt syndrome, Kashani-Strom-Utley syndrome, IBIDS syndrome, ICCA syndrome, ICE syndrome, ICF syn Kasznica carison coppedge syndrome, Katsantoni papadakou 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, Ilium 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, Kosztolanyi 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, tridogoniodysgen 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, Kussmaul-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, US 2010/0210539 A1 Aug. 19, 2010

Lamellar ichthyosis, Laminopathy, Landau-Kleffner Syn ataxia, Lutz-Richner-Landolt syndrome, Lyell syndrome, drome (LKS), Landing disease, Landouzy-Dejerine myopa Lyme borreliosis, Lyme disease, Lymphangioleiomyomato thy, Langer-Giedion syndrome, Langerhans cell granuloma sis, Lymphangioma, Lymphatic filariasis, Lymphatic malfor tosis, Langerhans cell histiocytosis, Langerhans cell mation, Lymphedema, Lymphocyte apoptosis anomaly, sarcoma, Laparoschisis, Laplane fontaine lagardere Syn Lymphocyte-depleted classical hodgkin lymphoma, Lym drome, Laron syndrome, Larsen syndrome, Larsen-like Syn phocyte-rich classical hodgkin lymphoma, Lymphocytic drome, Laryngeal abductor paralysis, Laryngo onycho cuta colitis, Lymphoid interstitial pneumonia, Lymphomatoid neous syndrome, Laryngo-tracheo-esophageal cleft granulomatosis, Lymphoproliferative disease associated with pulmonary hypoplasia, Lassa fever, Lassueur-Graham-Little primary immune disease, Lynch lee murday syndrome, syndrome, Late infantile neuronal ceroid lipofuscinosis, Late Lynch syndrome, Lyngstadaas Syndrome, Lysosomal dis onset sepsis in premature infants, Lathosterolosis, Laubry ease, Lytico-bodig disease, M-CMTC, M/SCHAD, MAD, peZZi Syndrome, Launois-Bensaude adenolipomatosis, Lau MADSAM, MAE, MALT lymphoma, MASA syndrome: rence-Moon syndrome, Laurin-Sandrow syndrome, MCA, MCAD deficiency, MCOPS1, MDC1A, MEB Lawrence syndrome, Lawrence-Seip syndrome, Laxova (Muscle-Eye-Brain) syndrome, MEHMO syndrome, Opitz Syndrome, Le Merrer syndrome, Le marec bracq MELAS, MEN 1, MEN 2, MERRF syndrome, MGA type I, picaud syndrome, Leao-da Silva syndrome, Learman syn MHBD deficiency, MIDD, MIRAS, MMEP syndrome, drome, Leber plus disease, Leber congenital amaurosis, MMND, MNGIE syndrome, MOSA syndrome, MOCOD, Leber miliary aneurysm, Left renal vein entrapment Syn MODY syndrome, MORM syndrome, MPPH syndrome, drome, Left ventricular hypertrabeculation, Left ventricular MPS, MRGH, MRKH syndrome, MRXS7, MSA, MTHFR noncompaction, Legg-Calve-Perthes disease, Legionellosis, deficiency, MVA syndrome, MYH9, MacDuffie's syndrome, Legionnaires disease, Leichtman-Wood-Rohn syndrome, Mac dermot winter syndrome, Maccario mena syndrome, Leifer lai buyse syndrome, Leigh disease, Leiner disease, Macdermot-Patton-Williams syndrome, Machado-Joseph Leiomyomatosis of esophagus cataract hematuria, Leiomyo disease, Macias flores garcia cruz rivera syndrome, Mackay 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 (LAAHO), 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 Lipoedema, 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 Luteinizing hormone releasing hormone deficiency with syndrome, Meacham winn culler syndrome, Meadows' Syn US 2010/0210539 A1 Aug. 19, 2010 22 drome, Meckel like syndrome, Meckel syndrome, Meckel plasia, Multiple fibrofolliculoma, Multiple hamartoma Gruber syndrome, Meconium aspiration syndrome, Medeira syndrome, Multiple keratoacanthoma, Multiple pterygium dennis donnai Syndrome, Mediastinal (thymic) large b-cell syndrome, Multiple sclerosis, Multiple sulfatase deficiency, lymphoma, Mediastinal diffuse large-cell lymphoma with Multiple system atrophy, Multiple ventricular septal defects, sclerosis, Mediastinal fibrosis, Medrano roldan syndrome, Mulvihill-Smith syndrome, MURCS association, Murray Medullar disease, Medullary cystic kidney disease, Medullo Puretic-Drescher syndrome, Muscular channelopathy, Mus blastoma, Megacalycosis, Megaduodenum and/or megacyS cular dystrophy, Muscular fibrosis multifocal obstructed ves tis, Megaloblastic anaemia, Megarbane-Loiselet syndrome, sels, Mutchinick syndrome, Myalgia eosinophilia associated Mehes syndrome, Mehta-Lewis-Patton syndrome, Meier with tryptophan, Myasthenia gravis, Myasthenic syndromes, blumberg imahorn syndrome, Meier-Gorlin syndrome, Mycetoma, Mycoplasma encephalitis, Mycosis fungoides, Meige disease, Meinecke pepper syndrome, Meinecke Syn Myelinoclastic diffuse sclerosis, Mvelinosis centralis diffusa, drome, Melanoma, Meleda disease, Melhem fahl syndrome, Myelocerebellar disorder, Myelodysplastic or myeloprolif Melioidosis, Melkersson rosenthal syndrome, Melnick erative disease, Myelofibrosis with myeloid metaplasia, Needles syndrome, Melorheostosis, Membranoproliferative Myeloid sarcoma, Myeloma, Myhre syndrome, Myiasis, glomerulonephritis, Membranous glomerulopathy, Menetri Myoclonic dystonia, Myoclonic epilepsy, Myodysplasia, er's disease, Mengel konigsmark syndrome, Meniere's dis Myofibrillar myopathy, Myoglobinuria, Myopathy and dia ease, Meningioma, Meningitis, Menkes syndrome, Mental betes mellitus, Myopathy, Myopia, Myositis ossificans pro retardation, Meretoja syndrome, Merkel cell carcinoma gressiva, Myotilinopathy, Myotonia congenita, Myotonic (MCC), Merlob grunebaum reisner syndrome, Mesangial disease, Myotubular myopathy, Myxofibrosarcoma, Myxoid sclerosis, Mesodermic dysplasia, Mesothelioma, Mesulam liposarcoma, Myxoid malignant fibrous histiocytoma, syndrome, Metabolic intoxication disease, Metabolic liver Myxoma with fibrous dysplasia, Möbius syndrome. N Syn disease, Metaphyseal dysplasia, Michels syndrome, Mickle drome, NACG, NAGS deficiency, NAME syndrome, NAO son syndrome, Micro syndrome, Microcephaly, Microcoria, syndrome, NARP syndrome, NASH syndrome, NBS, NCL, 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 najar 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, polydactyl), 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 US 2010/0210539 A1 Aug. 19, 2010 with eosinophilia, Non-infectious uveitis affecting the poste Paraneoplastic pemphigus, Paraneoplastic retinopathy, rior segment of the eye, Nonaka myopathy, Nondysgermi Paraplegia, Parathyroid carcinoma, Parenchymatous liver nomatous germ cell tumor, Noonan like contracture myopa disease, Paris-Trousseau thrombocytopenia, Parkes-Weber thy hyperpyrexia, Noonan like syndrome, Noonan syndrome, syndrome, Parkinson disease, Parkinsonism-dementia-ALS Normomorphic sialidosis, Norrie disease, Norum disease, complex, Paroxysmal cold haemoglobinuria, Paroxysmal Nova syndrome, Novak syndrome, Nuclear cell envelopathy, exertion-induced dyskinesia, Paroxysmal ventricular fibrilla O donnell pappas syndrome, O'Doherty syndrome, tion, Parry-Romberg syndrome, Parsonage-Turner Syn O'Sullivan-McLeod syndrome, OA-1, OCA, OCRL1, OFC drome, Partial deep dermal and full thickness burns, Parting syndrome, OFCD syndrome, OHSS, OLEDAID, ONMR ton amyloidosis, Partington disease, Partington-Anderson syndrome, OPPG, ORW 2, OSLAM syndrome, OSMED, syndrome, Partington-Mulley Syndrome, Parvovirus antena OTUDP syndrome, Obliterative portal venopathy, Occlusive tal infection, Pascual castroViejo syndrome, Pashayan Syn infantile arteriopathy, Occupational allergicalveolitis, Ochoa drome, Passwell-Goodman-Siprkowski syndrome, Patau syndrome, Ochronosis, Oculo skeletal renal syndrome, syndrome, Patterned dystrophy of the retinal pigment epithe Oculo-osteo-cutaneous syndrome, Oculoectodermal Syn lium, Patterson pseudoleprechaunism syndrome, Patterson drome, Oculogastrointestinal muscular dystrophy, Oculomo Stevenson syndrome, Patterson-Lowry rhizomelic dysplasia, tor palsy, Oculomotor paralysis, Oculopharyngodistal Pauciarticular chronic arthritis, Pavone fiumara rizzo syn myopathy, Odontologic disease, Odontomatosis, Oerter drome, Pearson syndrome, Peeling skin syndrome, Pelget Friedman-Anderson syndrome, Oesophageal atresia, Oguchi Huer anomaly, Pelizaeus-Merzbacher brain sclerosis, Pella disease, Ohaha syndrome, Ohdo madokoro Sonoda Syn gra, Pemphigus, Pena-Shokeir syndrome, Pendred drome, Ohtahara syndrome, Okamoto syndrome, Okihiro syndrome, Penta X syndrome, Pentosuria, Peptide metabo syndrome, Oligocone syndrome, Oligomeganephronia, lism disease, Peptidic growth factors deficiency, Perheentupa Oliver mcfarlane syndrome, Oliver syndrome, Oilier disease, syndrome, Periarteritis nodosa, Pericardial defect diaphrag Olmsted syndrome, Omenn Syndrome, Omodysplasia, Onat matic hernia, Pericarditis, Perineurioma, Peripartum cardi 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, Phytosteroiemia, 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 brachydactyl), 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 tyl), Polyepiphyseal dysplasia, Polymicrogyria, Polymorphic ease, Panniculitis, Panostotic fibrous dysplasia, Papillo-renal catecholergic ventricular tachycardia, Polymyositis, Polyos syndrome, Papillomatosis, recurrent respiratory, Papillon totic fibrous dysplasia, Polyposis, Polysyndactyly cardiac Leage-Psaume syndrome, Papillon-Lefevre Syndrome, Papu malformation, Pompe disease, Popliteal web syndrome, lar and Sclerodermoid lichen myxedematosus, Papular atri Porokeratosis, Porphyria, Portal hypertension, Portal vein chia, Papular mucinosis of infancy, Paramyotonia, thrombosis, Post polio syndrome, Post transplantation graft US 2010/0210539 A1 Aug. 19, 2010 24 dysfunction, Post-poliomyelitic syndrome, Post-transplant Weber disease, Renier-Gabreels-Jasper syndrome, Renpen lymphoproliferative disease, Post-traumatic syringomyelia, ning syndrome, Resistance to activated protein C, Resistance Postanginal sepsis secondary to orophyngeal infection, Pos to thyroid stimulating hormone, Respiratory bronchiolitis, terior cortical atrophy, Postpartum cardiomyopathy, Postviral Restless legs syndrome, Restrictive cardiomyopathy, Reticu Fatigue Syndrome, Potocki-Shaffer syndrome, Potter lar perineurioma, Retinal arteriolar tortuosity, Retinal degen sequence, Powell chandra Saal Syndrome, Powell Venencie eration, Retinal dystrophy, Retinal hemorrhage, Retinoblas gordon syndrome, Prader-Willi syndrome, Prata liberal gon toma, Retinohepatoendocrinologic syndrome, Retinopathy calves syndrome, Preauricular pits renal disease, Precursor of prematurity, Retinoschisis with early hemeralopia, Retin B-cell acute lymphoblastic leukaemia, Precursor T-cell acute oschisis, Retraction syndrome, Retroperitoneal fibrosis, Rett lymphoblastic leukaemia, Preeyasombat-Varavithya syn like syndrome, Rett syndrome, Revesz-Debuse syndrome, drome, Pregnancy-related cholestasis, Premature aging, Reye's syndrome, Reynolds syndrome, Rh deficiency syn Pressure-induced localized lipoatrophy, Prieto-Badia-Mulas drome, Rhabdomyosarcoma, Rheumatic fever, Rhizomelic syndrome, Prieur-Griscelli syndrome, Primary biliary cirrho dysplasia, Rhnull syndrome, Richards-Rundle syndrome, sis, Primary ciliary dyskinesia, Primary cutaneous CD30 Richardson's syndrome, Richieri Costa-Guion Almeida-Co positive T-cell lymphoproliferative disorders, Primary effu hen syndrome, Richieri costa da Silva syndrome, Richieri sion lymphoma, Primary effusion lymphoma associated with costa gorlin syndrome, Richieri-Costa-Colletto syndrome, the human immunodeficiency virus (HIV) infection, Primary RichieriCosta-Pereira syndrome, Richner-Hanhart syn intestinal lymphangiectasia, Primary lateral Sclerosis, Pri drome, Ricker syndrome, Rickettesiae disease, Riedel Thy mary lipodystrophy, Primary lymphoedema, Primary pulmo roiditis, Rieger syndrome, Right atrium familial dilatation, nary lymphoma, Primary Sclerosing cholangitis, Primerose Right ventricle hypoplasia, Rigid spine syndrome, Riley-Day syndrome, Progeria, Progressive bulbar paralysis of child syndrome, Riley-Smith syndrome, Rippberger aase Syn hood, Progressive cone dystrophy, Progressive diaphyseal drome, Rippling muscle disease, Ritscher Schinzel syndrome, dysplasia, Progressive massive osteolysis, Progressive neph Rivera-Perez-Salas syndrome, Roberts syndrome, Robinow 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 scoff 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 US 2010/0210539 A1 Aug. 19, 2010 drome, Scleroderma, Scleromyxedema, Sclerosing tonic dystrophy, Steinfeld syndrome, Stern-Lubinsky-Durrie mediastinitis, Sclerosteosis, Scott syndrome, Scott-Bryant syndrome, Stevens-Johnson syndrome, Stickler syndrome, Graham syndrome, Scott-Taor syndrome, Seaver cassidy Stiff person syndrome, Still disease, Stimmler syndrome, syndrome, Sebastian syndrome, Seckel like syndrome, Stoeling a de koomen davis syndrome, Stoll alembik finck Seckel syndrome, Sedlackova Syndrome, Seemanova lesny syndrome, Stoll geraudel Chauvin syndrome, Stollkieny dott syndrome, Segawa syndrome, Seghers syndrome, Seitel syndrome, Stoll-Levy-Francfort syndrome, Stomach cancer, berger disease, Selig-Benacerraf-Greene syndrome, Sellars Stormorken-Sjaastad-Langslet syndrome, Stratton garcia Beighton syndrome, Sengers syndrome, Sengers-Hamel-Of young syndrome, Stratton parker syndrome, Streptobacillo ten syndrome, Senior syndrome, Senior-Boichis syndrome, sis, Streptococcal toxic-shock syndrome, Stress cardiomyo Senior-Loken syndrome, Sensenbrenner syndrome, Senter pathie, Strumpell-Lorrain disease, Sturge-Weber syndrome, syndrome, Sepsis, Septic phlebitis of the internal jugular Stuve-Wiedemann dysplasia, Subcutaneous panniculitis-like vein, Sequeiros sack syndrome, Servelle-Martorell syn T-cell lymphoma, Subpulmonary Stenosis, Sucking/swallow drome, Setleis syndrome, Severe closed traumatic brain ing disorder, Sudden infant death syndrome, Sugarman Syn injury, Severe combined immunodeficiency T. B-. Severe drome, Sujansky-Leonard syndrome, Sulfocysteinuria, Sum combined immunodeficiency with hypereosinophilia, Severe merskill-Walshe-Tygstrup Syndrome, Summitt syndrome, combined immunodeficiency with leukopenia, Severe pneu Supravalvar aortic Stenosis, Susac syndrome, Sutton disease mococcemia, Sezary's lymphoma, Shapiro syndrome, II, Sweet syndrome, Swyer syndrome, Symphalangism, Syn Sharma kapoor ramji Syndrome, Sharp syndrome, Sheehan copal paroxysmal tachycardia, Syncopal tachyarythmia, syndrome, Shigellosis, Shokeir syndrome, Shone syndrome, Syndromatic diarrhea, Synovialosarcoma, Synovitis, Syn Short QT syndrome, Short bowel syndrome due to necrotiz spondylism, Syntelencephaly, Syringocystadenoma papil ing enterocolitis, Short bowel syndrome due to thrombosis, liferum, Syringomyelia, Systemic capillary leak syndrome, Short bowel syndrome, Shprintzen omphalocele syndrome, Systemic lupus erythematosus, Systemic mastocytosis, Sys Shprintzen-Goldberg syndrome, Shulman syndrome, temic scleroderma (systemic sclerosis), Systemic vasculitis, Shwachman-diamond syndrome, Shydrager syndrome, Siali T cell immunodeficiency, T-cell leukaemia, T-cell chronic dosis, Sickle cell anaemia, Sideroblastic anaemia, Sidransky lymphocytic leukaemia, TAC, TAR syndrome, TCP, TDO Feinstein-Goodman syndrome, Siegler brewer carey Syn syndrome, TEMF, TGA, TINU syndrome, TNF receptor 1 drome, Silengolerone pelizZo syndrome, Sillence syndrome, associated periodic syndrome, TOS, TRAPS syndrome, TTP, Simosa penchasZadeh bustos syndrome, Simpson dysmor TTR amyloid cardiopathy, TTR amyloid neuropathy, phia syndrome (SDYS), Simpson-Golabi-Behmel syndrome, Tabatznik syndrome, Takatsuki syndrome, Takayasuarteritis, Sinding-Larsen-Johansson disease, Singh chhaparwal Takotsubo cardiomyopathy, Tang hsi ryu syndrome, Tangier dhanda syndrome, Singh-Williams-McAlister syndrome, disease, Tardive dyskinesia, Tarsal Tunnel syndrome, Tarui Single ventricular septal defect, Singleton-Merten dysplasia, disease, Tauopathy, Taussig-Bing syndrome, Tay Syndrome, Singleton-Merten syndrome, Sino-auricular heart block, Tay-Sachs disease, Taybi syndrome, Taybi-Linder syndrome, Sinus node disease and myopia, Sipple syndrome, Sirenom Teebi al Saleh hassoon syndrome, Teebi kaurah syndrome, elia, Sitosterolemia, Situs inversus viscerum-cardiopathy, Teebi naguib alawadi syndrome, Teebi shaltout syndrome, Sjögren syndrome, Sjögren-Larsson syndrome, Skeletal dys Telangiectasia, Telecanthus, Telfer Sugar jaeger syndrome, plasia, Skeletal muscle disease, Skin collagen disease, Skin Temtamy-Shalash syndrome, Ter Haar syndrome, Teratoma, vascular disease, Sleep disorder, Sleeping seekness, Sly dis Tetraamelia, Tetralogy of Fallot, Thakker donnai syndrome, ease, Small bowel adenocarcinoma, Small bowel leiomyosa Thalassaemia syndrome, Thanatophoric dysplasia, The rcoma, Small non-cleaved cell lymphoma, Smith martin dodd odore's syndrome. Thiele Syndrome. Thiemann disease, syndrome, Smith-Fineman-Myers syndrome, Smith-Lemli Thies-Reis syndrome, Thomas jewett raines syndrome, Tho Opitz syndrome, Smith-Magenis syndrome, Sneddon Syn mas Syndrome, Thompson baraitser syndrome, Thomsen and drome, Sneddon-Wilkinson disease, Snyder-Robinson syn Becker disease, Thong douglas ferrante syndrome, Thoracic drome, Soft tissue perineurioma, Soft tissue sarcomas, aortic aneurysm and/or dissection, Thoracic outlet syndrome, Sohval soffer syndrome, Solitary plasmacytoma, Solomon Three M disease. Thromboangiitis obliterans, Thrombocyto syndrome, Somatotrophadenoma, Sommerhines syndrome, paenia, Thrombocytopenic purpura autoimmune, Thromb Sommer rathbun battles syndrome, Sommer-Young-Wee ocytopenic purpura idiopathic, Thrombocytosis, Throm Frye syndrome, Sondheimer syndrome, Sonoda syndrome, boembolic pulmonary hypertension, Thrombotic disease of Sorsby syndrome, Sorsby's fundus dystrophy, Sotos syn haematologic origin, Thymic aplasia, Thymic carcinoma, drome, Spastic paraplegia, Spellacy gibbs watts syndrome, Thyroid tumor, Tick-borne encephalitis, Tletze syndrome, Spherophakia-brachymorphia, Sphingolipidosis, Spina Timothy syndrome, Tollner horst manzke syndrome, Tolosa bifida, Spinal atrophy, Spirillosis, Splenic marginal Zone lym Hunt syndrome, Tomaculous neuropathy, Tome brune phoma, Spondylarthropathy, Spondylo camptodactyly Syn fardeau syndrome, Toni-Debré-Fanconi disease, Tonoki drome, Spondylocostal dysostosis, Spondyloenchondrodys Ohura-Niikawa syndrome, TORCH syndrome, Toriello syn plasia, Spondyloepiphyseal dysplasia, Spongy degeneration drome, Toriello-Carey syndrome, Toriello-Higgins-Miller of central nervous system, Spongy myocardium, Spontane syndrome, Toriello-Lacassie-Droste syndrome, Torres ayber ous pneumothorax familial type, Sporotrichosis, Squamous syndrome, Tourette syndrome, Townes-Brocks syndrome, cell carcinoma of head and neck, St Louis encephalitis, Toxocariasis, Toxoplasma embryopathy, Toxoplasmosis, Stalker chitayat Syndrome, Stampe Sorensen syndrome, Tracheopathia osteoplastica, Tranebaerg-SVeigaard Syn Stapedo-Vestibular ankylosis, Staphylococcal necrotizing drome, Transmissible spongiform encephalopathies, Trans pneumonia, Staphylococcal Scarlet fever, Staphylococcal position of the great arteries with pulmonary Stenosis, Tran toxic shock syndrome, Stargardt disease, Stark-Kaeser Syn sthyretin amyloid polyneuropathy, Treacher-Collins drome, Startle disease, Steatocystoma, Steele-Richardson syndrome, Aspiration pneumotitis requiring intubation and Olszewski disease, Stein-Leventhal syndrome, Steinert myo mechanical ventilation, Cardiogenic shock, Treft-Sanborn US 2010/0210539 A1 Aug. 19, 2010 26

Carey syndrome, Trench fever, Trevor disease, Triatrial heart, Wegener granulomatosis, Weil syndrome, Weill-Marchesani Trichinosis, Tricho onychic dysplasia, Tricho-dento-Osseous syndrome, Weismann Netter Stuhl syndrome, Weissen syndrome, Tricho-hepato-enteric syndrome, Trichorhinopha bacher-Zweymuller syndrome, Wellesley-Carman-French langeal, Trichorrhexis nodosa syndrome, Trichothiodystro syndrome, Wells syndrome, Wells-Jankovic syndrome, phy, Tricuspid atresia, Triopia, Triple A syndrome, Triple Werdnig-Hoffmann disease, Wermer syndrome, Werner syn H(HHH) syndrome, Triplo-X syndrome, Trisomy, Tritano drome, Wernicke's encephalopathy, Wernicke-Korsakoff pia, Trochlear dysplasia, Tropical calcific chronic pancreati syndrome, West syndrome, West-Nile encephalitis, Wester tis, Tropical endomyocardial fibrosis, Truebburg bottani syn hof-Beemer-Cormane syndrome, Western equine encephalo drome, Tsao-Ellingson syndrome, Tsukahara-Kaji myelitis, Westphall disease. Whelan syndrome. Whipple dis syndrome, Tsukuhara syndrome, Tsutsugamushi disease, ease. Whistling face syndrome, Whooping cough, Whyte Tsutsugamushi fever, Tuberculosis, Tuberous sclerosis, Murphy syndrome, Wieacker-Wolff syndrome, Wiedemann Tubular duplication of the oesophagus, Tubular dysplasia, grosse dibbern syndrome, Wiedemann oldigs oppermann Tubular renal disease—cardiomyopathy, Tubulointerstitial syndrome, Wiedemann-Beckwith syndrome, Wiedemann nephritis and uveitis syndrome, Tucker syndrome, Tuffli Rautenstrauch syndrome, Wildervanck syndrome, Wilkes Laxova Syndrome, Tularaemia, Tungiasis, Tungland-Beil Stevenson syndrome, Wilkie-Taylor-Scambler syndrome, man syndrome, Tunnel Subaortic Stenosis, Turcot syndrome, Willebrand disease, Willi-Prader syndrome, Williams syn Turner syndrome, Turner-Kieser syndrome, Twin.twin trans drome, Williams-Beuren syndrome, Wilms tumor, Wilson fusion syndrome, Tylosis, ULD, UPDM, UPDP, USH, Uhl disease, Wilson-Turner syndrome, Winchester disease, anomaly, Ulbright hodes syndrome, Ulcerative colitis, Winkelman bethge pfeiffer syndrome, Winkelmann's cytoph Ulerythema ophryogenesis, Ulick syndrome, Ullrich disease, agic panniculitis, Winship Viljoen leary syndrome, Winter Umbilical cord ulceration, Univentricular cardiopathy, harding hyde syndrome, Winter-Shortland-Temple syn Unverricht-Lundborg disease, Upington disease, Upshaw drome, Wiskott-Aldrich syndrome, Wissler-Fanconi syn Schulman syndrome, Urbach-Wiethe disease, Urban-Rog drome. Witkop syndrome. Wittwer syndrome, Wolcott-Ral ers-Meyer syndrome, Urban-Schosser-Spohn syndrome, lison syndrome, Wolf-Hirschhorn syndrome, Wolff Uremic pruritus, Urrets-Zavalia syndrome, Usher syndrome, Zimmermann syndrome, Wolff-Parkinson-White syndrome, Usual interstitial pneumonia (UIP), Uveitis, VIPoma, Wolfram syndrome, Wolman disease, Woodhouse Sakati syn VMCM, VODI syndrome, VSD, VWS, Vagneur triolle ripert drome, Woods black norbury syndrome, Woods leversha rog syndrome, Van Allen-Myhre syndrome, Van Benthem-Dries ers syndrome, Woods-Crouchman-Huson syndrome, Worster sen-Hanveld syndrome, Van Bogaert disease, VanDerWoude drought syndrome, Worth syndrome, Wrinkly skin syn syndrome, Vanbiervliet hendrickX Van ertbruggen syndrome, drome, Wyburn-Mason syndrome, XHIGM, XLAG syn Van de berghe-Dequeker syndrome, Van den Bosch syn drome, XMEA, XP, Xanthic urolithiasis, Xanthinuria, Xan drome, Van den ende brunner syndrome, Van der Knapp Syn thogranulomatous hypophysitis, Xanthomatosis drome, Van goethem syndrome, Van maldergem wetzburger cerebrotendinous, Xerocytosis, Xeroderma pigmentosum, verloes syndrome, Van regemorterpiercquin Vamos syndrome, Yellow fever, Yellow nail syndrome, Yersiniosis, Yorifuji Varadi-Papp syndrome, Vascular leukoencephalopathy, Vas Okuno syndrome, Yoshimura-takeshita syndrom, Young culitis, Vasquez-Hurst-Sotos syndrome, Vasterbotten dystro maders syndrome, Young syndrome, Young-Hugues Syn phy, Vein of Galen aneurysm, Venencie powell winkelmann drome, Young-Simpson syndrome, Yunis-Varon syndrome, syndrome, Ventricular septal defect, Ventricular septal defect ZASP-related myofibrillar myopathy, Zadik-Barak-Levin with aortic insufficiency, Verloes—Gillerot Fryns syn syndrome, Zellweger syndrome, Zellweger-like syndrome, drome, Verloes bourguignon syndrome, Verloes david Syn Zimmerphocomelia, Zimmerman laband syndrome, Zinsser drome, Verloes van maldergem marneffe Syndrome, Verloes Cole-Engman syndrome, Zlotogora-Ogur syndrome, Zlo Deprez syndrome, Verloove vanhorick brubakk syndrome, togura-MartineZ Syndrome, Zollinger-Ellison syndrome, Verneuil disease, Viljoen winship syndrome, Viljoen-Kallis Zori Stalker williams syndrome, Zunich-Kaye syndrome, Voges syndrome, Viljoen-Smart syndrome, Viral hemor Zygomycosis, 2.8 dihydroxy-adenine urolithiasis, 2-aminoa rhagic fever, Viral hepatitis, Viral vasculitis, Visceral neur dipic aciduria, 2-hydroxyglutaricaciduria, 2-methylbutyric opathy, Vitiligo, Vitreoretinal degeneration, Vogt-Koyanagi aciduria, 3 hydroxyisobutyric aciduria, 3-hydroxy-3-methyl Harada disease, Vohwinkel syndrome, Volcke-Soekarman glutaric aciduria, 3-methylcrotonylglycinuria, 3-methyl syndrome, Von Gierke disease, Von Hippel-Lindau disease, glutaconic aciduria, 3C syndrome, 3M syndrome, 4-hydroxy Von Recklinghausen disease, Von Voss-Cherstvoy syndrome, butyricaciduria, Visceral leishmaniasis, Vernal Von Willebrand disease, Von hippel anomaly, Vsr syndrome, keratoconjunctivitis, UV-A and visible light-induced photo Vuopala disease, W syndrome, WAGR syndrome, sensitivity disorders (chronic actinic dermatitis, cutaneous WARBM1, WHIM syndrome, WL syndrome, WT limb porphyrias, actinic prurigo and Solar urticaria), Uremic pru blood syndrome, Waaler-Aarskog syndrome, Waardenburg ritus, Tricyclic antidepressants poisoning, Traumatic spinal syndrome, Waardenburg-Shah Syndrome, Wagner disease, cord injury, Renal cell carcinoma, Superficial bladder cancer, Waisman syndrome, Waldenstrom macroglobulinemia, Staphylococcus aureus bacteraemia, Spinal cord injury, Waldmann disease, Walker-Dyson syndrome, Walker-War Spina bifida, Soft tissue sarcoma, Small cell lung cancer, burg syndrome, Wallis cremin beighton syndrome, Wallis Sickle cell disease, Severe myoclonic epilepsy in infancy, Zieff goldblatt syndrome, Warburg Micro syndrome, Warburg Severe combined immunodeficiency (SCID). Severe closed thomsen syndrome, Warburton-Anyane-Yeboa syndrome, traumatic brain injury, Retinopathy of prematurity, Retinitis Warman-Mulliken-Hayward syndrome, Water-West syn pigmentosa, Respiratory distress syndrome in premature neo drome, Waterhouse-Friedrickson syndrome, Watson syn nates of less than 32 weeks of gestational age, Recurrent drome, Weaver like syndrome, Weaver syndrome, Weaver hepatitis C virus induced liver disease in liver transplant Williams syndrome, Weber-Christian disease (WCD). recipients, Radiation proctitis, Pseudomonas aeruginosa Weber-Christian panniculitis, Webster deming syndrome, lung infection in cystic fibrosis, Progressive myoclonic epi US 2010/0210539 A1 Aug. 19, 2010 27 lepsies, Primary malignant bone tumors, Primary apnoea of intermittent porphyria, Active phase of Peyronie's disease, premature newborns, Post-transplant lymphoproliferative Acanthamoebakeratitis, A-mannosidosis, 5q spinal muscular disorders, Post-neonatal intracerebral haemorrhage, Post atrophy, Cavopulmonary Anastomosis, Atrial Septal Defects transplantation graft dysfunction, Polycythemia Vera, Peritu (ASD), Partial Anomalous Pulmonary Venous Return, Per moral oedema derived from brain tumors, Peripheral T-cell sistent Common Atrio Ventricular Canal Endocardial Cush lymphoma (nodal, other extranodal and leukaemic/dissemi ion Defect. Ostium Primum, Single Atrium, Patent Ductus nated), Ductus arteriosus in premature neonates of less than Arteriosus (PDA), Total Anomalous Pulmonary Venous 34 weeks of gestational age, Partial deep dermal and full Return, Ventricular Septal Defects (VSD), Pulmonary Valve thickness burns, Paroxysmal nocturnal haemoglobinuria, Stenosis, Pulmonary Artery Stenosis and Stenosis of Pulmo nary Artery Branches, Pulmonary Atresia with Intact Ven Pancreatic cancer, Painful HIV-associated neuropathy, Ova tricular Septum, Congenital Mitral Valve Disease, Aortic Val rian cancer, Osteosarcoma, Orthostatic hypotension in Vular Stenosis and Congenital Aortic Valvular Regurgitation, patients with pure autonomic failure, Orthostatic hypotension Supravalvular Aortic Stenosis, Transposition of the Great in patients with multiple system atrophy, Ornithine-transcar Arteries, Double Outlet Right Ventricle, Corrected Transpo bamylase deficiency, Oral mucositis in head and neck cancer sition of the Great Arteries, Truncus Arteriosus, Aorto Pul patients undergoing radiation therapy, Oesophageal cancer, monary Window, Tricuspid Atresia, Ebstein Anomaly, Mal Non-traumatic osteonecrosis, Non-ketotic hyperglyci formations of the Vena Cava, Coarctation of the Aorta, Atresia naemia, Non-infectious uveitis affecting the posterior seg of Aortic Valve, Anomalies of the Aortic Arch, Anomalous ment of the eye, Non-24-hour sleep-wake disorders in blind Origin of the Right Subclavian Artery with Coarctation of the people with no light perception, Neuroblastoma, Neovascular Aorta, Idiopathic Dilatation of the Pulmonary Artery, Left glaucoma, Nephritic syndrome, Myelodysplastic syndromes, Pulmonary Artery Arising from Right Pulmonary Artery, Myasthenia gravis, Moderate and severe traumatic brain Dextrocardia—Situs Inversus Totalis, Association of Heart injury, Metachromatic leukodystrophy, Medullary thyroid Malformations with Asplenia, Malformations of the Vena carcinoma, Mastocytosis, Mantle cell lymphoma, Malignant Cava, Congenital Coronary Artery Arterio-Venous Fistula, melanoma, Malignant gastrointestinal stromal tumors, Mal Abnormal Origin of the Coronary Arteries, Aneurysm of the absorption due to exocrine pancreatic enzyme insufficiency, Sinus of Valsalva (Aortic Sinus Aneurysm), Endocardial Low flow priapism, Lipoprotein lipase deficiency, Ligneous Fibroelastosis, Idiopathic Hypertrophic Subaortic Stenosis conjunctivitis, Leber's hereditary optic neuropathy, Leber's (IHSS), Mitral Valve Prolapse—Barlow's Syndrome, Hypo congenital amaurosis, Late onset sepsis in premature infants of less than or equal to 32 weeks gestational age, Juvenile plastic Left Heart. myelomonocytic leukaemia, Japanese encephalitis, Intestinal Pharmaceutical Compositions graft-Versus-host disease, Indolent non-Hodgkin's lym phoma, Inborn errors in primary bile acid synthesis, Hyper 0155 Still another aspect of the present invention relates phenylalaninemia, Hypereosinophilic syndrome, Glioma, to the use of the peptide according to claim 1 as an active High-grade dysplasia in Barrett's oesophagus, Herpes sim ingredient, together with at least one pharmaceutically plex virus stromal keratitis, Hereditary factor XIII deficiency, acceptable carrier, excipient and/or diluents for the manufac Hepatocellular carcinoma, Hepatitis B re-infection following ture of a pharmaceutical composition for the treatment and/or liver transplantation, Hepatic veno-occlusive disease, Gram prophylaxis of cancer, an autoimmune disease, a fibrotic dis negative bacterial lung infection in cystic fibrosis, Gastric ease, an inflammatory disease, a neurodegenerative disease, cancer, Gamma sarcoglycanopathy, Follicular lymphoma, an infectious disease, a lung disease, a heart and vascular Familial adenomatous polyposis, Emphysema secondary to disease or a metabolic disease or any other disease disclosed congenital alpha-1 antitrypsin deficiency, Duchenne muscu herein. lar dystrophy, Diffuse large B cell lymphoma, Diffuse alveo 0156 Such pharmaceutical compositions comprise the lar haemorrhage, Diarrhoea associated with intestinal peptide as an active ingredient, together with at least one microSporidial infection, Cutaneous T-cell lymphoma, Cuta pharmaceutically acceptable carrier, excipient, binders, dis neous forms of lupus erythematosus, Cushing's syndrome integrates, glidents, diluents, lubricants, coloring agents, secondary to ectopic ACTH secretion, Corneal graft rejec Sweetening agents, flavoring agents, preservatives or the like. tion, Congenital venous malformations, Congenital lym The pharmaceutical compositions of the present invention phatic malformations, Congenital alpha-1 antitrypsin defi can be prepared in a conventional Solid or liquid carrier or ciency, Congenital adrenal hyperplasia, Chronic pain, diluents and a conventional pharmaceutically-made adjuvant Cocaine poisoning, Chronic myeloid leukaemia, Chronic at Suitable dosage level in a known way. lymphocytic leukaemia, Chronic iron overload requiring che (O157 Preferably the peptide is suitable for intravenous lation therapy, Chronic idiopathic myelofibrosis, Chronic administration or suitable for oral administration or suitable eosinophilic leukaemia and the hypereosinophilic syndrome, for administration by inhalation. Cholangiocarcinoma, Charcot-Marie-Tooth disease type 1A, 0158 Administration forms include, for example, pills, Cardiogenic shock, Bronchopulmonary dysplasia in prema tablets, film tablets, coated tablets, capsules, liposomal for ture neonates of less than 30 weeks of gestational age, B-cell mulations, micro- and nano-formulations, powders and chronic lymphocytic leukemia, Autoimmune uveitis, Atypi deposits. Furthermore, the present invention also includes cal Haemolytic Uraemic Syndrome (aHUS) associated with pharmaceutical preparations for parenteral application, an inherited abnormality of the complement system, Aspira including dermal, intradermal, intragastral, intracutan, intra tion pneumonitis requiring intubation and mechanical venti Vasal, intravenous, intramuscular, intraperitoneal, intranasal, lation, Aneurysmal Subarachnoid haemorrhage, Anaplastic intravaginal, intrabuccal, percutan, rectal, Subcutaneous, Sub thyroid cancer, Anal fistula, Acute sensorineural hearing loss lingual, topical, or transdermal application, which prepara (acute acoustic trauma, Sudden deafness and Surgery induced tions in addition to typical vehicles and/or diluents contain the acoustic trauma), Acute peripheral arterial occlusion, Acute peptide according to the present invention. US 2010/0210539 A1 Aug. 19, 2010 28

0159. The present invention also includes the mammalian 0.165 Additionally, the compositions of the present inven milk, artificial mammalian milk as well as mammalian milk tion may be formulated in sustained release form to provide substitutes as a formulation for oral administration of the the rate controlled release of any one or more of the compo peptide to newborns, toddlers, and infants, either as pharma nents or active ingredients to optimize the therapeutic effects. ceutical preparations, and/or as dietary food Supplements. Suitable dosage forms for sustained release include layered 0160 The peptide of the invention can also be adminis tablets containing layers of varying disintegration rates or tered in form of its pharmaceutically active salts. Suitable controlled release polymeric matrices impregnated with the pharmaceutically active salts comprise acid addition salts and active components and shaped in tablet form or capsules alkali or earth alkali salts. For instance, Sodium, potassium, containing such impregnated or encapsulated porous poly lithium, magnesium or calcium salts can be obtained. meric matrices. 0161 The peptide of the invention forms pharmaceuti 0166 Aerosol preparations suitable for inhalation may cally acceptable salts with organic and inorganic acids. include solutions and Solids in powderform, which may be in Examples of suitable acids for such acid addition salt forma combination with a pharmaceutically acceptable carrier Such tion are hydrochloric acid, hydrobromic acid, Sulfuric acid, as inert compressed gas, e.g. nitrogen. phosphoric acid, acetic acid, citric acid, oxalic acid, malonic 0.167 For preparing Suppositories, a low melting wax Such acid, Salicylic acid, p-aminosalicylic acid, malic acid, as a mixture of fatty acid glycerides such as cocoa butter is fumaric acid, Succinic acid, ascorbic acid, maleic acid, Sul first melted, and the active ingredient is dispersed homoge fonic acid, phosphonic acid, perchloric acid, nitric acid, for neously therein by Stirring or similar mixing. The molten mic acid, propionic acid, gluconic acid, lactic acid, tartaric homogeneous mixture is then poured into convenient sized acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, molds, allowed to cool and thereby solidify. benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, 0168 Also included are solid form preparations which are methanesulfonic acid, ethanesulfonic acid, nitrous acid, intended to be converted, shortly before use, to liquid form hydroxyethanesulfonic acid, ethylenesulfonic acid, p-tolu preparations for either oral or parenteral administration. Such enesulfonic acid, naphthylsulfonic acid, Sulfanilic acid, cam liquid forms include Solutions, Suspensions and emulsions. pherSulfonic acid, china acid, mandelic acid, o-methylman 0169. The peptide of the present invention may also be delic acid, hydrogen-benzenesulfonic acid, picric acid, adipic deliverable transdermally. The transdermal compositions acid, D-o-tolyltartaric acid, tartronic acid, C-toluic acid, (o. may take the form of creams, lotions, aerosols and/or emul m, p)-toluic acid, naphthylamine Sulfonic acid, and other sions and can be included in a transdermal patch of the matrix mineral or carboxylic acids well known to those skilled in the or reservoir type as are conventional in the art for this purpose. art. The salts are prepared by contacting the free base form 0170 The transdermal formulation of the peptide of the with a sufficient amount of the desired acid to produce a salt invention is understood to increase the bioavailability of said in the conventional manner. peptide into the circulating blood. One problem in the admin 0162 The pharmaceutical compositions according to the istration of peptides is the loss of bioactivity due to the for present invention will typically be administered together with mation of insolubles in aqueous environments or due to deg suitable carrier materials selected with respect to the intended radation. Therefore stabilization of peptides for maintaining form of administration, i.e. for oral administration in the form their fluidity and maintaining their biological activity upon of tablets, capsules (either solid filled, semi-solid filled or administration to the patients in need thereof needs to be liquid filled), powders for constitution, aerosol preparations achieved. consistent with conventional pharmaceutical practices. Other 0171 Prior efforts to provide active agents for medication Suitable formulations are gels, elixirs, dispersible granules, include incorporating the medication in a polymeric matrix syrups, Suspensions, creams, lotions, solutions, emulsions, whereby the active ingredient is released into the systemic Suspensions, dispersions, and the like. Suitable dosage forms circulation. Known Sustained-release delivery means of for Sustained release include tablets having layers of varying active agents are disclosed, for example, in U.S. Pat. No. disintegration rates or controlled release polymeric matrices 4,235,988, U.S. Pat. No. 4,188,373, U.S. Pat. No. 4,100,271, impregnated with the active components and shaped in tablet U.S. Pat. No. 447,471, U.S. Pat. No. 4,474,752, U.S. Pat. No. form or capsules containing such impregnated or encapsu 4,474,753, or U.S. Pat. No. 4,478,822 relating to polymeric lated porous polymeric matrices. The pharmaceutical com pharmaceutical vehicles for delivery of pharmaceutically positions may be comprised of 5 to 95% by weight of the active chemical materials to mucous membranes. The phar peptide. maceutical carriers are aqueous solutions of certain polyoxy 0163 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 absorption 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 0164 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 0172 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 the peptide. Aside from serving as a stabilizer for benzoate, sodium acetate, Sodium chloride, and the like. Dis the peptide, poloxamers provide excellent vehicles for the integrants include starch, methylcellulose, guar gum and the delivery of the peptide, and they are physiologically accept like. Sweetening and flavoring agents and preservatives may able. Poloxamers, also known by the trade name Pluronics also be included where appropriate. Some of the terms noted (e.g. Pluronic F127, Pluronic P85, Pluronic F68) have surfac above, namely disintegrants, diluents, lubricants, binders and tant properties that make them useful in industrial applica the like, are discussed in more detail below. tions. Among other things, they can be used to increase the US 2010/0210539 A1 Aug. 19, 2010 29 water solubility of hydrophobic, oily substances or otherwise 0181. In addition to the nutritional components, breast increase the miscibility of two substances with different milk contains a wealth of bioactive components that have hydrophobicities. For this reason, these polymers are com beneficial non-nutritional functions. These include a wide monly used in industrial applications, cosmetics, and phar range of specific and non-specific antimicrobial factors; maceuticals. They have also been used as model systems for cytokines and anti-inflammatory Substances; and hormones, drug delivery applications. In situ gelation of pharmaceutical growth modulators, and digestive enzymes (Table 1), many of compositions based on poloxamer that are biologically trig which have multiple activities. These components may be of 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. 0173 The term capsule refers to a special container or enclosure made of methyl cellulose, polyvinyl alcohols, or TABLE 1 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 sules are typically made of blends of relatively high gel Antimicrobial factors strength bone and pork skin gelatins. The capsule itself may Secretory IgA, IgM, IgG contain Small amounts of dyes, opaquing agents, plasticizers lactoferrin lysozyme and preservatives. complement C3 0.174 Tablet means compressed or molded solid dosage leucocytes form containing the active ingredients with Suitable diluents. bifidus factor The tablet can be prepared by compression of mixtures or lipids and fatty acids 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-inflammatory factors 0175 Oral gels refers to the active ingredients dispersed or solubilized in a hydrophilic semi-solid matrix. tumor necrosis factor interleukins 0176 Powders for constitution refer to powder blends 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) insulin 0177 Human breast milk is a complex fluid, rich in nutri prolactin ents and in non-nutritional bioactive components. It contains thyroid hormones all of the nutrients needed by the newborn baby. These corticosteroids include the metabolic components (fat, protein, and carbohy ACTH Oxytocin drates), water, and the raw materials for tissue growth and calcitonin development, such as fatty acids, amino acids, minerals, Vita parathyroid hormone mins, and trace elements. erythropoietin (0178 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 epidermal (EGF) fatty acids in breastmilk triglycerides, with comparatively nerve (NGF) high proportions of the essential fatty acids, and linolenic insulin-like (IGF) acid, followed by long-chain polyunsaturated fatty acids, transforming (TGF) aurine Such as arachidonic acid and docosahexaenoic acid. These polyamines long-chain fatty acids are constituents of brain and neural Digestive enzymes tissue and are needed in early life for mental and visual development. The lipid component of breast milk is the trans amylase bile acid-stimulating esterase port vehicle for fat-soluble micronutrients such as prostag bile acid-stimulating lipases landins and vitamins A, D, E, and K. ipoprotein lipase (0179 Proteins account for approximately 75% of the Transporters nitrogen-containing compounds in breast milk. Non-protein actoferrin (Fe) nitrogen Substances include urea, nucleotides, peptides, free olate binder amino acids, and DNA. The proteins of breast milk can be 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 0182 Besides breast milk, infant formula is the only other albumin, with a large number of other proteins and peptides infant milk which the medical community considers nutri present in Smaller amounts. tionally acceptable for infants under the age of one year. 0180. The principal carbohydrate is lactose, a disaccha Cow's milk is not recommended because of its high protein ride produced in the mammary epithelial cell from glucose by and electrolyte (salt) content which may harm infant’s imma a reaction involving lactalbumin. ture kidneys. The nutrient content of infant formula should US 2010/0210539 A1 Aug. 19, 2010 30 comprise: Protein, Fat, Linoleic acid, Vitamins: A, C, D, E, K, Sodium carboxymethyl starch, natural and synthetic gums thiamin (B1), riboflavin (B2), B6, B12, Niacin, Folic acid, Such as locust bean, karaya, guar, tragacanth and agar, cellu Pantothenic acid, Calcium, Metals: magnesium, iron, Zinc, lose derivatives such as methylcellulose and Sodium car manganese, copper, Phosphorus, Iodine, Sodium chloride, boxymethylcellulose, microcrystalline celluloses and cross Potassium chloride. In addition, formulas not made with linked microcrystalline celluloses such as sodium cow’s milk must include biotin, choline, and inositol. croScarmellose, alginates such as alginic acid and sodium Hypoallergenic formulas reduce the likelihood of certain alginate, clays such as bentonites, and effervescent mixtures. medical complications in babies with specific health prob The amount of disintegrant in the composition can range from lems. Baby formula can be synthesized from raw amino acids. This kind of formula is sometimes referred to as elemental about 1 to about 40% by weight of the composition, prefer infant formula or as medical food because of its specialized ably 2 to about 30% by weight of the composition, more nature. 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. 0191 Binders characterize substances that bind or “glue' 0183 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 0184 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 0185. 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 0.192 Lubricant refers to a substance added to the dosage between the powder particles. form to enable the tablet, granules, etc. after it has been 0186 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 0187 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'l- 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 0188 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 powerform the peptide of the present invention. The peptide position, more preferably from about 0.3 to about 3%, and is preferably added in an amount of 3-100 ug peptide or per most preferably from about 0.3 to about 1.5% by weight of the 100 ml (commercially available) mother milk formulation, composition. more preferably in an amount of 5-70 g/100 ml and most 0193 Glidents are materials that prevent caking and preferably in an amount of 10-40 pg/100 ml mother milk improve the flow characteristics of granulations, so that flow formulation. is Smooth and uniform. Suitable glidents include silicon diox 0189 Suitable diluents are substances that usually make ide and talc. The amount of glident in the composition can up the major portion of the composition or dosage form. range from about 0.01 to 10% by weight of the composition, Suitable diluents include Sugars such as lactose, Sucrose, preferably 0.1% to about 7% by weight of the total composi mannitol and sorbitol, starches derived from wheat, corn rice tion, more preferably from about 0.2 to 5% by weight, and and potato, and celluloses such as microcrystalline cellulose. most preferably from about 0.5 to about 2% by weight. The amount of diluents in the composition can range from 0194 Coloring agents are excipients that provide colora about 5 to about 95% by weight of the total composition, tion to the composition or the dosage form. Such excipients preferably from about 25 to about 75%, more preferably from can include food grade dyes and food grade dyes adsorbed about 30 to about 60% by weight, and most preferably from onto a Suitable adsorbent such as clay or aluminum oxide. The about 40 to 50% by weight. amount of the coloring agent can vary from about 0.01 to 10% 0190. The term disintegrants refers to materials added to by weight of the composition, preferably from about 0.05 to the composition to help it break apart (disintegrate) and 6% by weight, more preferably from about 0.1 to about 4% by release the medicaments. Suitable disintegrants include weight of the composition, and most preferably from about starches, “cold water soluble” modified starches such as 0.1 to about 1%. US 2010/0210539 A1 Aug. 19, 2010

0.195 The peptide of the invention can be used to form (0199 Preferred is the group of carboxylic acid buffers multiparticulates, discrete particles, well known dosage Such as acetate and carboxylic diacid buffers such as fuma forms, whose totality represents the intended therapeutically rate, tartrate and phthalate and carboxylic triacid buffers such useful dose of a drug. When taken orally, multiparticulates as citrate. Another group of preferred buffers is represented generally disperse freely in the gastrointestinal tract, and by inorganic buffers such as Sulfate, borate, carbonate, maximize absorption. A specific example is described in U.S. oxalate, calcium hydroxyde and phosphate buffers. Another Pat. No. 6,068,859, disclosing multiparticulates that provide group of preferred buffers are nitrogen containing buffers controlled release of azithromycin. Another advantage of the Such as imidazole, diethylenediamine, and piperazine. multiparticulates is the improved stability of the drug. The 0200 Also preferred are sulfonic acid buffers such as TES, poloxamer component of the multiparticulate is very inert, HEPES, ACES, PIPES, (2-hydroxy-1,1-bis(hydroxym ethyl)ethyl)amino-1-propanesulfonic acid (TAPS), 4-(2-hy thus minimizing degradation of the drug. droxyethyl)piperazine-1-propanesulfonic acid (EPPS), 0196. 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 0201 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 0202 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, tryptophans, 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, peptide 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 0.197 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, 3.2-52 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) 0198 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 6.0-8.0 6.35 carbonate (pK1) (pKa2=4.76, pKa2=6.4), glutamate buffer (pKa=4.3), phos 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 (0203 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. US 2010/0210539 A1 Aug. 19, 2010 32

The effective pH range for each buffer can be defined as blood for intravenous administration or lung tissue for inha pKa-1 to pKa+1, where Ka is the ionization constant for the lation administration. Thus it is preferred that the rehydrated weak acid in the buffer and pKa=-log K. formulation is substantially isotonic. 0204 Most preferred are buffers suitable for pharmaceu 0212. The preferred dosage concentration for either intra tical use e.g. buffers suitable for administration to a patient venous, oral, or inhalation administration is between 100 to Such as acetate, carbonate, citrate, fumarate, glutamate, lac 2000 umole/ml, and more preferably is between 200 to 800 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 in the mother milk substitute or artificial mother milk formu ers are acetate buffer, citrate buffer, glutamate buffer and lation or the pharmaceutical compositions disclosed herein. phosphate buffer. Also most preferred is the group of car boxylic acid buffers. The term "carboxylic acid buffers’ as Dietary Supplement used herein shall refer to carboxylic mono acid buffers and carboxylic diacid buffers as well as carboxylic triacid buffers. 0213 Still another aspect of the present invention relates Of course also combinations of buffers, especially of the to the use of disclosed peptide as a dietary Supplement. That buffers mentioned herein are useful for the present invention. dietary Supplement is preferably for oral administration and 0205 Some suitable pharmaceutical buffers are a citrate especially but not limited to administration to newborns, tod buffer (preferably at a final formulation concentration of from dlers, and/or infants. A dietary Supplement is intended to about 20 to 200 mM, more preferably at a final concentration supplement the diet. The “dietary ingredients’ in these prod of from about 30 to 120 mM) or an acetate buffer (preferably ucts may in addition include: Vitamins, minerals, herbs or at a final formulation concentration of about 20 to 200 mM) or other botanicals, amino acids, and Substances Such as a phosphate buffer (preferably at a final formulation concen enzymes, organ tissues, glandulars, and metabolites. Dietary tration of about 20 to 200 mM). Supplements may be manufactured in forms such as tablets, 0206 Techniques for the formulation and administration capsules, softgels, gelcaps, liquids, or powders. of the peptide of the present invention may be found in “Rem ington's Pharmaceutical Sciences’ Mack Publishing Co., Method of Treatment Easton Pa. A Suitable composition comprising the peptide mentioned herein may be a solution of the peptide in a Suit 0214) Another aspect of the present invention relates to a able liquid pharmaceutical carrier or any other formulation method of prophylaxis and/or treatment of cancer, an autoim such as tablets, pills, film tablets, coated tablets, dragees, mune disease, a fibrotic disease, an inflammatory disease, a capsules, powders and deposits, gels, syrups, slurries, Suspen neurodegenerative disease, an infectious disease, a lung dis sions, emulsions, and the like. ease, a heart and vascular disease or a metabolic disease or 0207. 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 Leu-Leu-Gly-Asp-Phe-Phe-Arg-Lys administration. To prepare the preferred lyophilised prepara Ser-Lys-Glu-Lys-Ile-Gly-Lys-Glu-Phe-Lys-Arg-Ile-Val tion the peptide of the invention are solubilised in a 4 to 5% Gln-Arg-Ile-Lys-Asp-Phe-Leu-Arg-Asn-Leu-Val-Pro-Arg (w/v) mannitol solution and the solution is then lyophilised. Thr-Glu-Ser-NH in a therapeutically effective amount The mannitol Solution can also be prepared in a Suitable effective to treat the afore-mentioned disease. buffer solution as described above. 0215. Accordingly, the terms “prophylaxis' or “treat 0208 Further examples of suitable cryo-flyoprotectants ment includes the administration of the peptide of the (otherwise referred to as bulking agents or stabilizers) include present invention to prevent, inhibit, or arrest the symptoms thiol-free albumin, immunoglobulins, polyalkyleneoxides of an infectious disease, an autoimmune disease, a fibrotic (e.g. PEG, polypropylene glycols), trehalose, glucose, disease, an inflammatory disease, a neurodegenerative dis Sucrose, Sorbitol, dextran, maltose, raffinose, stachyose and ease, or a heart and vascular disease. In some instances, other saccharides (cf. for instance WO97/29782), while man treatment with the peptide of the present invention will be nitol is used preferably. These can be used in conventional done in combination with other protective compounds to amounts in conventional lyophilization techniques. Methods prevent, inhibit, or arrest the symptoms of an infectious dis of lyophilisation are well known in the art of preparing phar ease, an autoimmune disease, a fibrotic disease, an inflam maceutical formulations. matory disease, a neurodegenerative disease, or a heart and 0209 For administration by inhalation the particle diam vascular disease. eter of the lyophilised preparation is preferably between 2 to 0216. The term “active agent” or “therapeutic agent’ as 5 Lim, more preferably between 3 to 4 lum. The lyophilised used herein refers to an agent that can prevent, inhibit, or preparation is particularly Suitable for administration using arrest the symptoms and/or progression of an infectious, an an inhalator, for example the OPTINEB(R) or VENTA-NEB(R) autoimmune disease, a fibrotic disease, an inflammatory dis inhalator (NEBU-TEC, Elsenfeld, Germany). The lyophi ease, a neurodegenerative disease, or a heart and vascular lised product can be rehydrated insterile distilled water or any disease or any other disease disclosed herein. other suitable liquid for inhalation administration. 0217. The term “therapeutic effect” as used herein, refers 0210 Alternatively for intravenous administration the to the effective provision of protection effects to prevent, lyophilised product can be rehydrated insterile distilled water inhibit, or arrest the symptoms and/or progression of an infec or any other Suitable liquid for intravenous administration. tious, an autoimmune disease, a fibrotic disease, an inflam 0211. After rehydration for administration in sterile dis matory disease, a neurodegenerative disease, or a heart and tilled water or another suitable liquid the lyophilised prepa vascular disease. ration should have the approximate physiological osmolality 0218. The term “a therapeutically effective amount’ as of the target tissue for the rehydrated peptide preparation i.e. used herein means a sufficient amount of the peptide of the US 2010/0210539 A1 Aug. 19, 2010

invention to produce atherapeutic effect, as defined above, in 0224. As used herein “mimic' is defined as an increase in a subject or patient in need of treatment. the activity of a biological pathway dependent on the under 0219. The terms “subject” or “patient” are used herein produced biological molecule of between 10 to 100%. More mean any mammal, including but not limited to human preferably the increase of the activity of the biological path beings, including a human patient or Subject to which the way is between 25 to 100%. Even more preferably the compositions of the invention can be administered. The term increase of the activity the biological pathway is between 50 mammals include human patients and non-human primates, to 100%. as well as experimental animals such as rabbits, rats, and mice, and other animals. Peptide 0220. The peptide of the present invention can be used for 0225. The peptide of the invention was for tested for the the prophylaxis and/or treatment of cancer, an autoimmune activity as a therapeutic agent for the prophylaxis and/or disease, a fibrotic disease, an inflammatory disease, a neuro treatment of cancer, an infectious disease, an autoimmune degenerative disease, an infectious disease, a lung disease, a disease, a fibrotic disease, an inflammatory disease, a neuro heart and vascular disease or a metabolic disease or any other degenerative disease, or a heart and vascular disease: disease mentioned herein in combination administration with peptide having the amino acid sequence: another therapeutic compound. As used herein the term “combination administration of a compound, therapeutic agent or known drug with the peptide of the present invention Leu-Leu-Gly-Asp-Phe-Phe-Arg-Lys-Ser-Lys-Glu-Lys means administration of the drug and the peptide at Such time that both the known drug and the peptide will have a thera Ile-Gly-Lys-Glu-Phe-Lys-Arg-Ile-Val-Gln-Arg-Ile peutic effect. In some cases this therapeutic effect will be Lys-Asp-Phe-Leu-Arg-Asn-Leu-Val-Pro-Arg-Thr-Glu synergistic. Such concomitant administration can involve concurrent (i.e. at the same time), prior, or Subsequent admin Ser-NH2. (LL-37). istration of the drug with respect to the administration of the peptide of the present invention. A person of ordinary skill in 0226. The term “LL-37 in brackets after the peptide the art would have no difficulty determining the appropriate sequence Leu-Leu-Gly-Asp-Phe-Phe-Arg-Lys-Ser-Lys-Glu timing, sequence and dosages of administration for particular Lys-Ile-Gly-Lys-Glu-Phe-Lys-Arg-Ile-Val-Gln-Arg-Ile drugs and peptide of the present invention. Lys-Asp-Phe-Leu-Arg-Asn-Leu-Val-Pro-Arg-Thr-Glu-Ser NH is an abbreviation or synonym of said peptide. Definition of Peptide Activity 0227 Furthermore the present invention relates to the use of the above-mentioned peptide as pharmaceutically active 0221) A peptide is deemed to have therapeutic activity if it agents in medicine, i.e. as medicament. Advantage of the demonstrated any one of the following activities listed in a) to peptide of the invention is that the peptide is less toxic in g). comparison to the commonly used drugs for the certain indi a) The peptide could inhibit the activity of an over active cations mentioned herein and that the peptide have less side biological pathway. effects, can be used for a long term treatment of certain b) The peptide could inhibit the production of an over pro diseases and can be easily administered. Moreover the pep duced biological molecule. tide are selective for certain targets and under physiological c) The peptide could inhibit the activity of an over produced conditions no toxic or noxious degradation products are biological molecule. formed. d) The peptide could increase the activity of an under active 0228. As used herein, the term "peptide(s) or “peptide(s) biological pathway. of the invention' shall also refer to salts, deprotected form, e) The peptide could increase the production of an under acetylated form of the peptide, deacetylated form of the pep produced biological molecule. tide, enantiomers, diastereomers, racemates, prodrugs and f) The peptide could mimic the activity of an under produced hydrates of the above-mentioned peptide. Diastereomers of biological molecule. the peptide are obtained when the stereochemical or chiral g) The peptide could prevent, inhibit, or arrest the symptoms center of one or more amino acids is changed. The enantiomer and/or progression of cancer, an infectious disease, an has the opposite Stereochemistry at all chiral centers. autoimmune disease, a fibrotic disease, an inflammatory dis 0229. The term “prodrug” refers to any precursor com ease, a neurodegenerative disease, or a heart and vascular pound which is able to generate or to release the above disease or any other disease disclosed herein. mentioned peptide under physiological conditions. Such pro 0222. As used herein “inhibition' is defined as a reduction drugs, i.e. Such precursor molecules are for instance larger of the activity or production of a biological pathway or mol peptides which are selectively cleaved in order to form the ecule activity of between 10 to 100%. More preferably the peptide of the invention. Further prodrugs are protected reduction of the activity or production of a biological pathway amino acids having especially protecting groups at the car or molecule activity is between 25 to 100%. Even more pref boxylic acid and/or amino group. erably the reduction of the activity or production of a biologi 0230. Suitable protecting groups for amino groups are the cal pathway or molecule activity is between 50 to 100%. benzyloxycarbonyl, t-butyloxycarbonyl (BOC), formyl, and 0223. As used herein “increase' is defined as an increase acetyl or acyl group. Suitable protecting groups for the car of the activity or production of a biological pathway or mol boxylic acid group are esters such as benzyl esters or t-butyl ecule of between 10 to 100%. More preferably the increase of esterS. the activity or production of a biological pathway or molecule 0231. The present invention also includes the above pep activity is between 25 to 100%. Even more preferably the tide having amino acid Substitutions, deletions, additions, the increase of the activity or production of a biological pathway Substitutions and additions including the standard D and L or molecule activity is between 50 to 100%. amino acids and modified amino acids such as for example US 2010/0210539 A1 Aug. 19, 2010 34 amidated and acetylated amino acids, wherein the therapeutic pended at 5x10" cells/ml in tissue culture medium and added activity of the base peptide sequence as shown above is main to the peptide-containing microtiter plates in a Volume of 50 tained. microliters. 0232. In the listed peptide sequences Ac' indicates an 0236. The virus used was the lymphocytotropic strain acetylated residue and “NH indicates an amidated residue, HIV-1. Virus was obtained from NIH AIDS Research and “cyclo” indicates a cyclic peptide, and “D’ indicates a D Reference Reagent Program and was grown in CEM-SS cells optical isomer. Deacetyled amino or NH-group refers to the for the production of stock virus pools. For each assay, a free amino (—HH) group. pre-titered aliquot of virus was removed from the freezer (-80°C.) and allowed to thaw slowly to room temperature in TABLE 3 a biological safety cabinet. The virus was resuspended and diluted into tissue culture medium such that the amount of The following abbreviations are used for the virus added to each well in a volume of 50 microliters was the common amino acids referred to herein. amount determined to give between 85% to 95% cell killing Abbreviation Amino acid after 6 days post-infection. TCIDso calculations by endpoint Ala Alanine titration in CEM-SS cells indicated that the multiplicity of Arg Arginine infection was approximately 0.01. AZT (nucleoside reverse ASn Asparagine transcriptase inhibitor; NRTI) and indinavir (protease inhibi Asp Aspartic acid (Aspartate) tor; PI) were used as positive control antiviral compounds. Cys Cysteine Gln Glutamine Plate Format Glu Glutamic acid (Glutamate) Gly Glycine 0237 Each plate contained cell control wells (cells only), His Histidine virus control wells (cells plus virus), drug cytotoxicity wells Ile Isoleucine (cells plus peptide only), peptide colorimetric control wells Leu Leucine (peptide only) as well as experimental wells (peptide—10 Lys Lysine Met Methionine micrograms per ml plus cells plus virus). Samples were Phe Phenylalanine evaluated for antiviral efficacy with triplicate measurements Pro Proline and with duplicate measurements to determine cellular cyto Pyl Pyrrolysine toxicity, if detectable. Ser Serine Sec Selenocysteine 0238. At assay termination, the plates were stained with Thr Threonine the soluble tetrazolium-based dye MTS (CelTiter 96 Trp Tryptophan Reagent, Promega) to determine cell viability and quantify Tyr Tyrosine Wal Valine peptide toxicity. MTS is metabolized by the mitochondrial ASX Aspartic acid or Asparagine enzymes of metabolically active cells to yield a soluble for Glx Glutamine or Glutamic acid mazan product, allowing the rapid quantitative analysis of Xaa Any amino acid cell viability and peptide cytotoxicity. This reagent is a stable, Xle Leucine or Isoleucine single solution that does not require preparation before use. At assay termination, 20-25 microliters of MTS reagent was 0233 Some modified amino acids are indicated as fol added per well and the microtiter plates were then incubated lows: for 5 hours at 37° C., and 5% CO to assess cell viability. “D-2-NaI is 2-naphthyl-D-alanine, Adhesive plate sealers were used in place of lids, the sealed “SertBu” is t-butyl serine, plates were inverted several times to mix the soluble forma “AZagly’ is aza glycine, Zan product and the plate was read spectrophotometrically at “Me' is methyl, 49%60 nm with a Molecular Devices Vmax plate reader. Met(O) is methionine sulfoxide, 0239. The overall assay performance was valid based “Pyr' and “pGlu’ are pyroglutamic acid, upon judgement of the positive control compounds AZT and “Tyr(SO3H) is sulphated tyrosine, indinavir exhibiting the expected levels of antiviral activity. “Tyr(Me)' is methyltyrosine, Macroscopic observation of the cells in each well of the “NHEt” is ethylamide. microtiter plate confirmed the cytotoxicity results obtained following staining of the cells with the MIS metabolic dye. EXAMPLES 0240 Results from HIV experiments: 0234. The peptides as listed above were tested for activity using the assays described in Examples 1 to 17. The tested peptides are all commercially available. % CPE reduction in HIV-1 infected % Cell Example 1 Compound CEM-SS cells viability LL-37 46.5 86.4 HIV-1 Experiments AZT (positive control) 99 97 0235 CEM-SS cells were passaged in T-75 flasks prior to Indinavir (positive control) 1OO 93 use in the antiviral assay. On the day preceding the assay, the cells were split 1:2 to assure they were in an exponential growth phase at the time of infection. Total cell viability Example 2 quantification was performed using a hemacytometer and HBV Experimental Assay System trypan blue exclusion. Cell viability was greater than 95% for 0241 HepG2-2.2.15 is a stable cell line containing the the cells to be utilized in the assay. The cells were resus hepatitis B virus (HBV) ayw strain genome (ATCC Cat. No. US 2010/0210539 A1 Aug. 19, 2010

CRL-1 1997). Antiviral compounds blocking any late step of 0248 MRC-5 cells were seeded at 75,000 cells/well in 24 viral replication Such as transcription, translation, pregenome well plates using MRC-5 growth medium. The plates were encapsidation, reverse transcription, particle assembly and incubated overnight at 37° C., 5% CO. The following day, release can be identified and characterized using this cell line. media was removed and 100 plaque forming units (pfu) of In this assay, an active compound will reduce the production HCMV was added to the wells. Virus was allowed to adsorb of secreted HBV from cells, measured by utilizing real time onto the cells for 1 hour at 37° C., 5% CO. Peptide was quantitative PCR (TaqMan) assay to directly and accurately diluted—10 micrograms per ml in assay medium contain measure HBV DNA copies. The analysis of this data allows to ing 0.5% Methylcellulose. After the incubation period, 1 ml calculate: of each peptide solution was added to the wells without aspi 0242 Antiviral activity rating the virus inoculums. The plates were incubated for 0243 Compound Cytotoxicity 7-10 days to allow for plaque formation. Ganciclovir was 0244 HepG2-2.2.15 cells were plated in 96-well microti used as positive control. Cultures were examined microscopi ter plates. After 16-24 hours the confluent monolayer of cally and toxicities were noted. The media was the aspirated HepG2-2.2.15 cells was washed and the medium was from the wells and the cells were fixed and stained using 20% replaced with complete medium containing test peptide-10 methanol containing Crystal Violet followed by enumeration micrograms per ml in duplicate. Lamivudine (3TC) was of plaques by microscopic inspection. used as the positive control, while media alone was added to 0249 For cytotoxicity testing, MRC-5 cells were seeded the cells as a negative control (virus control). Three days later at 2,500 cells/well in 96 well plates using growth medium. the culture medium was replaced with fresh medium contain The plates were incubated overnight at 37°C., 5% CO. The ing the peptide. Six days following the initial administration following day, peptide was added and tested in duplicates. of the peptide, the cell culture Supernatants was collected, After a 6 days incubation period, cell viability was measured treated with pronase and DNAse and then used in a real-time using CellTiter96 Solution (Promega). Plates were incubated quantitative TaqMan PCR assay. The PCR-amplified HBV for additional 4 hours at 37°C. Adhesive plate sealers were DNA was detected in real-time by monitoring increases in used in place of lids, the sealed plates were inverted several fluorescence signals that result from the exonucleolytic deg times to mix the soluble formazan product and the plate was radation of a quenched fluorescence probe molecule that read spectrophotometrically at 49%60 nm with a Molecular hybridizes to the amplified HBV DNA. For each PCR ampli Devices Vmax plate reader. fication, a standard curve was simultaneously generated using 0250. The overall assay performance was valid based dilutions of purified HBV DNA. Antiviral activity was calcu upon judgement of the positive control compound Ganciclo lated from the reduction in HBV DNA levels (% virus con vir exhibiting the expected levels of antiviral activity. Mac trol). A novel dye uptake assay was then employed to measure roscopic observation of the cells in each well of the microtiter cell viability, which is used to calculate toxicity (% cell con plate confirmed the cytotoxicity results obtained following trol). staining of the cells with the MTS metabolic dye. 0245 Results from HBV experiments: (0251 Results from HCMV assay:

% inhibition of % plaque % Cell HBV replication % Cell Compound reduction viability Compound in HEP G2 cells viability LL-37 O.O 1OO LL-37 16.9 100 Ganciclovir (positive control) 1OO 1OO 3TC (positive control) 92.0 95.8

Example 3 Example 4 HCMV Experimental Assay System Methicillin Resistant Staphylococcus Aureus (MRSA) Assay 0246 MRC-5 cells (human embryonal lung fibroblasts) were obtained from the American Type Culture Collection 0252. The antibacterial assay was conducted using clear, (ATCC CCL-171; Rockville, Md.) and grown in Eagle's U-bottom 96-well microtiter plates. Cation-adjusted Muel Minimum Essential Medium with Earle's BSS (EMEM) ler-Hinton Broth (MHB) was used for testing MRSA. The supplemented with 10% fetal bovine serum (FBS), 0.1 mM peptide of the invention (0.1 ml of each—10 micrograms per non-essential amino acids, 1.0 mMSodium pyruvate, 2.0 mM ml ) was dispensed into wells in duplicate. Then the wells L-Glutamine, 100 units/ml Pencillin and 100 micrograms/ml were inoculated with 5x10 CFU/ml, MRSA in 0.1 ml vol Streptomycin. Cells were split twice a week 1:2. ume. For control purposes, each plate included 4 wells con 0247 HCMV strain AD 169 was obtained from ATCC taining media without bacterial inoculum and 4 wells con (ATCC VR-538). Virus stocks were prepared by infecting taining medium with inoculum but without peptide. The 80% confluent MRC-5 cells at a minimal multiplicity of plates were incubated for 12 h at 37° C., and read visually infection in MRC-5 growth medium containing 29/s FBS. 18-24 hours post-incubation. Growth control of MRSA was Monolayers were incubated at 37° C., 5% CO, until 90%- examined first to determine adequacy of media preparations 95% viral cytopathic effect (CPE) was observed (10-13 days). and growth conditions. Acceptable growth is defined as a 2 Culture medium was then collected from the cells, centri mm wide button of cells at the bottom of each sample well, or fuged at low speed to remove cellular debris, aliquoted in 1 ml obvious turbidity in the culture supernatant. Test wells were Volumes and stored at -80° C. as stock virus. examined and scored as positive/negative for activity. A posi US 2010/0210539 A1 Aug. 19, 2010 36 tive score for activity is based on complete inhibition of 0257 Results from Streptococcus pneumoniae Assay: macroscopic growth of the test MRSA. 0253) Results from MRSA Assay: Compound % inhibition

LL-37 O.O Compound % inhibition

LL-37 O.O Example 7 Example 5 Mycobacterium tuberculosis Assay Pseudomonas aeruginosa Assay 0258. The antibacterial assay was conducted using clear, 0254 The antibacterial assay was conducted using clear, U-bottom 96-well microtiter plates. Middlebrook 7H12 assay U-bottom 96-well microtiter plates. Cation-adjusted Muel medium was used for testing drug-resistant Mycobacterium ler-Hinton Broth (MHB) was used for testing Pseudomonas tuberculosis. The peptide of the invention (0.1 ml of each— aeruginosa. The peptide of the invention (0.1 ml of each—10 10 micrograms per ml ) was dispensed into wells in dupli micrograms per ml ) was dispensed into wells in duplicate. cate. Then the wells were inoculated with 5x10 CFU/mL Then the wells were inoculated with 5x10 CFU/mL Mycobacterium tuberculosis in 0.1 ml volume. For control Pseudomonas aeruginosa in 0.1 ml Volume. For control pur purposes, each plate included 4 wells containing media with poses, each plate included 4 wells containing media without out bacterial inoculum and 4 wells containing medium with bacterial inoculum and 4 wells containing medium with inoculum but without peptide. The plates were incubated for inoculum but without peptide. The plates were incubated for seven days at 37° C., and read visually thereafter. Growth 12 hat 37°C., and read visually 18-24 hours post-incubation. control of Mycobacterium tuberculosis was examined first to Growth control of Pseudomonas aeruginosa was examined determine adequacy of media preparations and growth con first to determine adequacy of media preparations and growth ditions. Acceptable growth is defined as a 2 mm wide button conditions. Acceptable growth is defined as 2 mm wide button of cells at the bottom of each sample well, or obvious turbidity of cells at the bottom of each sample well, or obvious turbidity in the culture Supernatant. Test wells were examined and in the culture Supernatant. Test wells were examined and scored as positive/negative for activity. A positive score for scored as positive/negative for activity. A positive score for activity is based on complete inhibition of macroscopic activity is based on complete inhibition of macroscopic growth of the test Mycobacterium tuberculosis. The drug growth of the test Pseudomonas aeruginosa. resistant Mycobacterium tuberculosis that was used in the 0255 Results from Pseudomonas aeruginosa Assay: assay is resistant against following medicaments: para-ami nosalicylic acid (PAS), streptomycin and isoniazid (INH). 0259 Results from Mycobacterium tuberculosis Assay: Compound % inhibition

LL-37 O.O Compound % inhibition

LL-37 O.O Example 6 Streptococcus pneumoniae Assay Example 8 0256 The antibacterial assay was conducted using clear, U-bottom 96-well microtiter plates. Cation-adjusted Muel Cell Cycle Assay ler-Hinton Broth (MHB) was used for testing Streptococcus pneumoniae. The peptide of the invention (0.1 ml of each— 0260 Human A549 cells (carcinomic human alveolar 10 micrograms per ml ) was dispensed into wells in dupli basal epithelial cells) were utilized in the experiments cate. Then the wells were inoculated with 5x10 CFU/mL employing the Propidium iodide cell cycle assay. The eukary Streptococcus pneumoniae in 0.1 ml Volume. For control otic cell cycle is a series of events that take place in a cell purposes, each plate included 4 wells containing media with leading to its replication. out bacterial inoculum and 4 wells containing medium with 0261 The regulation of the cell cycle involves steps cru inoculum but without peptide. The plates were incubated for cial to the cell, including detecting and repairing genetic 12 hat 37°C., and read visually 18-24 hours post-incubation. damage, and provision of various checks to prevent uncon Growth control of Streptococcus pneumoniae was examined trolled cell division. The molecular events that control the cell first to determine adequacy of media preparations and growth cycle are ordered and directional; that is, each process occurs conditions. Acceptable growth is defined as 22 mm wide in a sequential fashion. button of cells at the bottom of each sample well, or obvious 0262 The cell cycle consists of four distinct phases: G, turbidity in the culture supernatant. Test wells were examined phase, S phase, G2 phase (collectively known as interphase) and scored as positive/negative for activity. A positive score and M phase. M phase is itself composed of two tightly for activity is based on complete inhibition of macroscopic coupled processes: mitosis, in which the cell's chromosomes growth of the test Streptococcus pneumoniae. are divided between the two daughter cells, and cytokinesis, US 2010/0210539 A1 Aug. 19, 2010 37 in which the cell's cytoplasm divides forming distinct cells. 0266 Results from T cell proliferation assay: Activation of each phase is dependent on the proper progres sion and completion of the previous one. Cells that have temporarily or reversibly stopped dividing are said to have % of PHA entered a state of quiescence called Go phase. The relatively Compound induced control brief Mphase consists of nuclear division and cytoplasmic division. The first phase within interphase, from the end of the LL-37 96.8 previous M. phase till the beginning of DNA synthesis is called G (Gindicating gap or growth). During this phase the Example 10 biosynthetic activities of the cell resume at a high rate. This phase is marked by Synthesis of various enzymes that are B Cell Proliferation Assay required in S phase, mainly those needed for DNA replica tion. The ensuing S phase starts when DNA synthesis com 0267 Human Peripheral Blood Mononuclear Cells mences; when it is complete, all of the chromosomes have (PBMC) were obtained from normal human donors. The B cell proliferation was induced by stimulation of the cells with been replicated. The cell then enters the G phase, which lasts the B cell mitogen Staphylococcus aureus Cowans I (SAC) until the cell enters mitosis. Significant protein synthesis plus Interleukin-2, either in the absence (positive prolifera occurs during this phase, mainly involving the production of tion control), or in the presence of test peptide-10 micro microtubules, which are required during the process of mito grams per ml to examine their effects on the B cell response. sis. Inhibition of protein synthesis during G2 phase prevents 10/well PBMC were plated in 96-well microtiter plates and the cell from undergoing mitosis. assayed in duplicate with the peptide. Cell cultures were 0263. Disregulation of the cell cycle components may lead incubated at 37°C. for 3 days in a 5% CO incubator and were to tumor formation. Propidium iodide is an intercalating thereafter pulsed with 1 microCi/well H-thymidine for addi agent and a fluorescent molecule that can be used to stain tional 12 hours of culture. At the end of incubation time, the DNA. Cells were incubated for 24 hours with test peptide— plates were harvested and the cells counted by liquid scintil 10 micrograms per ml or left untreated. After that cells were lation for the incorporation of H-thymidine as a measure of trypsinized, suspended in medium+10% FCS, centrifuged B cell proliferation. (1000 rpm, 5min), and the cell pellet resuspended in PBS (1 0268 Results from B cell proliferation assay: ml). The cells were pipetted into 2.5 ml absolute EtOH (final concentration approx. 70%) and incubated on ice for 15 min. Thereafter, cells were pelleted at 1500 rpm for 5 min and % of SACIL2 resuspended in Propidium iodide solution in PBS. After incu Compound induced control bation for 40 min at 37°C., cells were analyzed in the FACS. LL-37 66.9 0264. Results from Cell Cycle Assay:

Example 11 Cell cycle analysis Phagocytosis Assay Compound GOG1 S G2FM 0269 RAW264.7 (Mouse leukaemic monocyte macroph LL-37 SO.6 47.4 2.0 age cell line) cells were obtained from ATCC and grown in RPMI 1640 medium containing 10% FBS. Cells were incu bated in 12x75 mm tubes at 37° C. with test peptide-10 Example 9 micrograms per ml for 30 min prior to adding Fluorescein labeled Escherichia coli bacteria as the agent to be ingested. T Cell Proliferation Assay After the cells were incubated for additional 60 min at 37° C. and allowed to ingest the Fluorescein-labeled. Escherichia 0265 Human Peripheral Blood Mononuclear Cells coli bacteria, cells were fixed with 1% paraformaldehyde. (PBMC) were obtained from normal human donors. The T The samples were then analyzed by flow cytometry to deter cell proliferation was induced by stimulation of the cells with mine the amount of phagocytosis as a function of brightness the T cell mitogen phytohemagglutinin (PHA), either in the (the greater the phagocytic activity, the more fluorescence in absence (positive proliferation control), or in the presence of the macrophage population). Data are reported as % positive test peptide-10 micrograms per ml to examine their and the mean fluorescence intensity (MFI) of positively effects on the T cell proliferating response. 10/well PBMC stained cells. were plated in 96-well microtiter plates and assayed in dupli 0270. Results from phagocytosis assay: cate with the peptide. Cell cultures were incubated at 37°C. for 3 days in a 5% CO, incubator and were thereafter pulsed with 1 microCi/well H-thymidine for additional 12 hours of % of control culture. At the end of incubation time, the plates were har Compound phagocytosis vested and the cells counted by liquid scintillation for the incorporation of H-thymidine as a measure of T cell prolif LL-37 1143 eration. US 2010/0210539 A1 Aug. 19, 2010 38

Example 12 Example 14 Apoptosis Induction Assay Th1/Th2 Cytokine Profiling Assay 0271 Human A549 cells (carcinomic human alveolar basal epithelial cells) were utilized in the experiments 0275 The Balb/c mice (originated in 1923, it is a popular employing the Annexin-5 apoptosis assay. Annexin-5 is a strain and is used in many different research disciplines. Also member of a highly conserved protein family that binds acidic classified as an inbred from the production of 20 or more phospholipids in a calcium-dependent manner. Annexin-5 possesses a high affinity for phosphatidylserine. Phosphati Successive brother-sister matings, the Balb/c mouse is albino dylserine is translocated from the inner side of the plasma and small in size) were immunized on Days 1, 15, and 29 with membrane to the outer layer when cells undergo death by Ovalbumin (Ovalbumin is the main protein found in egg apoptosis or cell necrosis and serves as a signal by which cell white, commonly used to stimulate an immunological reac destined for death are recognized by phagocytes. Test pep tion in test animals) in PBS (5 micrograms/injection). On day tide-10 micrograms per ml were exposed for 24 hours to 50, spleens of the mice were harvested (3 weeks after last the A549 cells before they were analyzed for signs of apop boost with Ovalbumin). Cells were cultured (2x10/well in tosis. triplicate) and incubated with culture medium or test pep 0272 Results from apoptosis induction assay: tide—10 micrograms per ml for 30 min. Thereafter, addi tional Ovalbumin was added to the cells at 10 micrograms/ml for in vitro restimulation of the cells. 72 hours later, cell Compound % of induction Supernatants were harvested and assayed using the Becton LL-37 O.2 Dickinson Mouse Th1/Th2 Cytokine CBA Kit. This kit can be used to measure Interleukin-2 (IL-2), Interleukin-4 (IL-4), Interleukin-5 (IL-5), Interferon-Y (IFN-Y), and Tumor Necro Example 13 sis Factor-O. (TNF-C.) protein levels in a single sample. The kit performance has been optimized for analysis of physiologi Apoptosis Prevention Assay cally relevant concentrations (pg/ml levels) of specific cytok 0273 Human A549 cells (carcinomic human alveolar ine proteins in tissue culture Supernatants and serum samples. basal epithelial cells) were utilized in the experiments (0276 Results from Th1/Th2 Cytokine assay:

TNF-a spleen cells; IFNY spleen cells; IL-2 IL-4 spleen cells; IL-5 spleen cells; TH1 response TH1 response spleen cells TH2 response TH2 response Compound (% of control) (% of control) (% of control) (% of control) (% of control) LL-37 37.0 21.2 172.1 O.O 74.1 employing the Annexin-5 apoptosis assay. Annexin-5 is a Example 15 member of a highly conserved protein family that binds acidic TNF Alpha Production Assay phospholipids in a calcium-dependent manner. Annexin-5 (0277 Human Peripheral Blood Mononuclear Cells possesses a high affinity for phosphatidylserine. Phosphati (PBMC) were obtained from normal human donors. The macrophages were prepared by adherence of PBMC to the dylserine is translocated from the inner side of the plasma plastic wells of the plates. After 8 days in culture in the membrane to the outer layer when cells undergo death by presence of recombinant human macrophage-colony Stimu apoptosis or cell necrosis and serves as a signal by which cell lating factor at 2 ng/ml, differentiated macrophages were destined for death are recognized by phagocytes. A549 cells preincubated with test peptide—10 micrograms per ml for were pretreated for 30 min with test peptide—10 micrograms 30 min, followed by in-well stimulation by the addition of lipopolysaccharide at a final concentration of 200 ng/ml. Not per ml followed by the exposure to C2 ceramide. Ceramide stimulated macrophages served as negative background con mediates cell apoptosis through the activation of the mitogen trol. activating protein kinase (MAPK) and the stress activated 0278 After overnight incubation, supernatants from the kinase (JNK/SAPK). C2 ceramide is a synthetic, membrane control and LPS-stimulated cultures were harvested and soluble analog of ceramide. assayed for TNF alpha production employing a TNF alpha 0274 Results from apoptosis prevention assay: specific ELISA. (0279 Results from TNFalpha assay:

% prevention of ceramide Compound induced apoptosis Compound % of LPS induction LL-37 O.O LL-37 6.8 US 2010/0210539 A1 Aug. 19, 2010 39

Example 16 Example 18 Endothelial Cell Migration Assay Mother Milk Formulation 0284 Methods to prepare mother milk or artificial mother 0280 Endothelial cell migration is a prerequisite for the milk formulations or mother milk substitutes are described in process of neo-vascularization orangiogenesis which is cru WO03043429, U.S. Pat. No. 5,962,062, WO0030461, cial for on-site recruitment of blood vessel formation. Pri EP0527283, EP0832565 mary Human endothelial cells (HUVEC) were seeded in 0285 One example of an artificial mother milk or mother insert chambers with 3 micrometer pore size of multi-tran milk substitute formulation is provided in the following while swell plate for 6 hours at 37° C. in Endothelial Cell Basal also the other formulations disclosed in the above mentioned Medium (EBM) supplemented with 0.1% bovine serum albu references can be used and are included herewith by refer min. Thereafter, designated concentration of test peptide-10 CCC. micrograms per ml was added in duplicate wells. The 0286 The milk substitute contains, by weight, approxi mately 15% skimmed milk solids, approximately 75% dem endothelia were allowed to migrate for 22 hours at 37° C. ineralized water, approximately 9%. Soya oil, approximately then, migrated cells were fixed and stained with Hoechst 0.02% of carrageenates, 0.2% lecithin, and approximately 33342 dye. Images of 3 fields per insert were taken and the 0.2% of disodium hydrogenphosphate. number of migrated cells per field were quantified using the 0287. In a first step, the solubilizing aqueous medium is ImageProPlus software. Data were analyzed for the average produced, comprises, by weight, approximately 75% of number of the migrated cells and standard deviation of six water, approximately 0.02% of carrageenate and approxi data points for each treatment condition. Active test peptide mately 0.2% of disodium hydrogenphosphate. against HUVEC migration was determined based on 50% 0288 The skimmed milk powder is then added to the inhibition of migrated cells as compared with the control. solution for 10 min at 60° C. and dissolved in the liquid. Statistic p values were computed using the Student's t-test. 0289. Then soya oil and lecithin are added to the milk 0281 Results from endothelial cell migration assay: substitute composition at 60° C. The milk composition is allowed to stand 30 min at 55° C. After pasteurization, the peptide of the invention is added in liquid or powder form in Such a quantity that the milk composition obtained comprises % inhibition of an amount of 5-50 micrograms, preferably 10-40 micrograms Compound migration per 100 ml of milk composition. Optionally peptide 2 could LL-37 O be added in similar or Smaller amounts to the obtained com position.

Example 17 Example 19 Gel Formulation Endothelial Tube Formation Assay 0290 0.5g of peptide 0282. The endothelial tube formation assay is based on the 1.6 g of isopropanol ability of endothelial cells to form three-dimensional capil 1.0 g of glycerol lary-like tubular structures when cultured on a gel of base 1.6 g of polyoxyethylene-polyoxypropylene copolymer ment membrane extract. The endothelial tube formation 12500 (Pluronic F127) assay represents a powerful model for studying inhibition and 5.3.g. of water induction of angiogenesis. Pre-labeled HUVEC with Calcein are mixed for 10 minutes and then heated to 85°C. under AM were seeded in a 96-well culture plate coated with extra continuous stirring for 15 minutes. The solution is cooled to cellular metrix (Chemicon international Cat. ECM625) and room temperature under stirring. During the cooling phase treated with test peptide-10 micrograms per ml in full the solution begins to gel at a temperature of about 45° C. to growth medium. Positive control wes vehicle only. The form a clear gel. The gel contains 5% of the peptide 1 for endothelial cells were allowed to form tubes foe 20 hours and medical use. Optionally peptide 2 could be added in an were then examined under an inverted fluorescent micro amount form 0.01 to 0.5g. Scope. Duplicate wells for each treatment were photographed and quantitatively analyzed for an average tubule length using Example 20 image analysis software ImageProPlus. Raw data were Lotion Formulation expressed as average tubule lengths in pixelsistandard devia tion. Statistic p values were computed using the Student's 0291 0.5g of peptide t-teSt. 1.9 g of isopropanol 1.0 g of dimethylisosorbide 0283 Results from endothelial tube formation assay: 1.0 g of polyoxyethylene-polyoxypropylene copolymer 12500 (Pluronic F127) 5.6 g of water % inhibition of are stirred and heated at 50° C., until a clear solution has been Compound tube formation formed. Then the composition is cooled to room temperature LL-37 32 under stirring. The lotion contains 5% of peptide 1 for medi cal use. Optionally peptide 2 could be added in an amount form 0.01 to 0.5g. US 2010/0210539 A1 Aug. 19, 2010 40

SEQUENCE LISTING

<16O is NUMBER OF SEO ID NOS : 1

<21Os SEQ ID NO 1 <211 > LENGTH: 37 <212> TYPE PRT <213> ORGANISM: Homo sapiens <22O > FEATURE: <221 > NAME/KEY: MOD RES <222> LOCATION: (37) . . (37) <223s OTHER INFORMATION: AMIDATION

<4 OOs, SEQUENCE: 1 Lieu. Lieu. Gly Asp Phe Phe Arg Llys Ser Lys Glu Lys Ile Gly Lys Glu 1. 5 1O 15 Phe Lys Arg Ile Val Glin Arg Ile Lys Asp Phe Lieu. Arg Asn Lieu Val 2O 25 Pro Arg Thr Glu Ser 35

1-12. (canceled) or hydrates thereof, wherein administration of the pharma 13. A pharmaceutical composition comprising a peptide ceutical composition treats said diseases. consisting of the sequence Leu-Leu-Gly-Asp-Phe-Phe-Arg 19. The method of claim 18, wherein the cancer, autoim Lys-Ser-Lys-Glu-Lys-Ile-Gly-Lys-Glu-Phe-Lys-Arg-Ile mune disease, fibrotic disease, inflammatory disease, neuro Val-Gln-Arg-Ile-Lys-Asp-Phe-Leu-Arg-Asn-Leu-Val-Pro degenerative disease, infectious disease, lung disease, heart Arg-Thr-Glu-Ser-NH. (SEQID NO:1). and vascular disease and metabolic disease is selected from B 14. The pharmaceutical composition of claim 13, wherein cell lymphomas, Epstein-Barr virus induced mononucleosis, said composition is incorporated in a nutritional formulation. systemic lupus erythematosis, autoimmune lymphoprolifera 15. The pharmaceutical composition of claim 14, wherein tive disease, lupus nephritis, dermatomyositis, lupus nephri the nutritional formulation is an artificial mother milk formu tis, rheumatic fever, polyglandular syndromes, Henoch lation or mother milk substitute suitable for oral administra Schonlein purpura, post-Streptococcal nephritis, erythema tion to newborns, toddlers and infants. nodosum, Takayasu's arteritis, sarcoidosis, erythema multi 16. The pharmaceutical composition of claim 13, wherein forme, IgA nephropathy, polyarteritis nodosa, Goodpasture's said composition is prepared as a lyophilized formulation or syndrome, thromboangitis ubiterans, primary biliary cirrho a buffered liquid formulation. sis, thyrotoxicosis, pulmonary fibrosis, sarcoidosis, chronic 17. The pharmaceutical composition of claim 13, wherein active hepatitis, polymyositis, dermatomyositis, polychon said composition comprises at least one pharmaceutically dritis, pamphigus Vulgaris, Wegener's granulomatosis, tabes acceptable carrier, cryoprotectant, lyoprotectant, excipient or dorsalis, giant cell arteritis, polymyalgia, pernicious anemia, diluent. rapidly progressive glomerulonephritis, fibrosing alveolitis, 18. A method of treatment of cancer, autoimmune disease, thrombocytopenias, rejection of any organ transplant or graft fibrotic disease, inflammatory disease, neurodegenerative Versus-host disease after a bone marrow transplant. disease, infectious disease, lung disease, heart and vascular 20. The method of claim 18, wherein the peptide is admin disease and metabolic disease, the method comprising, istered by intravenous administration, oral administration, or administering to a patient in need thereof, a therapeutically administration by inhalation. effective amount of a pharmaceutical composition compris 21. The method of claim 18, wherein the peptide is admin ing a peptide consisting of the sequence Leu-Leu-Gly-Asp istered as a lyophilized formulation or as a buffered liquid Phe-Phe-Arg-Lys-Ser-Lys-Glu-Lys-Ile-Gly-Lys-Glu-Phe formulation. Lys-Arg-Ile-Val-Gln-Arg-Ile-Lys-Asp-Phe-Leu-Arg-Asn Leu-Val-Pro-Arg-Thr-Glu-Ser-NH. (SEQ ID NO: 1) or salts