US 2010O2.10567A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0210567 A1 Bevec (43) Pub. Date: Aug. 19, 2010

(54) USE OF ATUFTSINASATHERAPEUTIC Publication Classification AGENT (51) Int. Cl. A638/07 (2006.01) (76) Inventor: Dorian Bevec, Germering (DE) C07K 5/103 (2006.01) A6IP35/00 (2006.01) Correspondence Address: A6IPL/I6 (2006.01) WINSTEAD PC A6IP3L/20 (2006.01) i. 2O1 US (52) U.S. Cl...... 514/18: 530/330 9 (US) (57) ABSTRACT (21) Appl. No.: 12/677,311 The present invention is directed to the use of the peptide compound Thr-Lys-Pro-Arg-OH as a therapeutic agent for (22) PCT Filed: Sep. 9, 2008 the prophylaxis and/or treatment of cancer, autoimmune dis eases, fibrotic diseases, inflammatory diseases, neurodegen (86). PCT No.: PCT/EP2008/007470 erative diseases, infectious diseases, lung diseases, heart and vascular diseases and metabolic diseases. Moreover the S371 (c)(1), present invention relates to pharmaceutical compositions (2), (4) Date: Mar. 10, 2010 preferably inform of a lyophilisate or liquid buffersolution or artificial mother milk formulation or mother milk substitute (30) Foreign Application Priority Data containing the peptide Thr-Lys-Pro-Arg-OH optionally together with at least one pharmaceutically acceptable car Sep. 11, 2007 (EP) ...... O7017754.8 rier, cryoprotectant, lyoprotectant, excipient and/or diluent. US 2010/0210567 A1 Aug. 19, 2010

USE OF ATUFTSNASATHERAPEUTIC ment of Hepatitis BVirus infection, diseases caused by Hepa AGENT titis B Virus infection, acute hepatitis, chronic hepatitis, full minant liver failure, liver cirrhosis, cancer associated with Hepatitis B Virus infection. 0001. The present invention is directed to the use of the Cancer, Tumors, Proliferative Diseases, Malignancies and peptide compound Thr-Lys-Pro-Arg-OH (Tuftsin) as a thera their Metastases peutic agent for the prophylaxis and/or treatment of cancer, 0008. The term "cancer as used herein refers also to autoimmune diseases, fibrotic diseases, inflammatory dis tumors, proliferative diseases, malignancies and their eases, neurodegenerative diseases, infectious diseases, lung metastases. Examples for cancer diseases are adenocarci diseases, heart and vascular diseases and metabolic diseases. noma, choroidal melanoma, acute leukemia, acoustic neuri noma, ampullary carcinoma, anal carcinoma, astrocytoma, BACKGROUND OF THE INVENTION basal cell carcinoma, pancreatic cancer, desmoid tumor, blad der cancer, bronchial carcinoma, non-Small cell lung cancer 0002 The identification of a therapeutic compound effec (NSCLC), breast cancer, Burkitt's lymphoma, corpus cancer, tive for the prophylaxis and/or treatment of a disease can be CUP-syndrome (carcinoma of unknown primary), colorectal based on the activity of the compound in a biological assay. A cancer, Small intestine cancer, Small intestinal tumors, ova biological assay that mimics a disease causative mechanism rian cancer, endometrial carcinoma, ependymoma, epithelial can be used to test the therapeutic activity of a candidate cancertypes, Ewing's tumors, gastrointestinal tumors, gastric peptide. cancer, gallbladder cancer, gallbladder carcinomas, uterine 0003. The causative mechanism of many diseases is the cancer, cervical cancer, cervix, glioblastomas, gynecologic over activity of a biological pathway. A peptide that can tumors, ear, nose and throat tumors, hematologic neoplasias, reduce the activity of the biological pathway can be effective hairy cell leukemia, urethral cancer, skin cancer, skin testis in the prophylaxis and/or treatment of the disease caused by cancer, brain tumors (gliomas), brain metastases, testicle can the over activity of the biological pathway. Similarly the cer, hypophysis tumor, carcinoids, Kaposi's sarcoma, laryn causative mechanism of many diseases is the over production geal cancer, germ cell tumor, bone cancer, colorectal carci of a biological molecule. A peptide that can reduce the pro noma, head and neck tumors (tumors of the ear, nose and duction of the biological molecule or block the activity of the throat area), colon carcinoma, craniopharyngiomas, oral can over produced biological molecule can be effective in the cer (cancer in the mouth area and on lips), cancer of the prophylaxis and/or treatment of the disease caused by the central nervous system, liver cancer, liver metastases, leuke over production of the biological molecule. mia, eyelid tumor, lung cancer, lymph node cancer 0004 Conversely, the causative mechanism of many dis (Hodgkin’s/Non-Hodgkin’s), lymphomas, stomach cancer, eases is the under activity of a biological pathway. A peptide malignant melanoma, malignant neoplasia, malignant tumors that can increase the activity of the biological pathway can be gastrointestinal tract, breast carcinoma, rectal cancer, effective in the prophylaxis and/or treatment of the disease medulloblastomas, melanoma, meningiomas, Hodgkin's dis caused by the under activity of the biological pathway. Also ease, mycosis fungoides, nasal cancer, neurinoma, neuroblas similarly the causative mechanism of many diseases is the toma, kidney cancer, renal cell carcinomas, non-Hodgkin’s under production of a biological molecule. A peptide that can lymphomas, oligodendroglioma, esophageal carcinoma, increase the production of the biological molecule or mimic osteolytic carcinomas and osteoplastic carcinomas, osteosa the biological activity of the under produced biological mol rcomas, ovarial carcinoma, pancreatic carcinoma, penile can ecule can be effective in the prophylaxis and/or treatment of cer, plasmocytoma, squamous cell carcinoma of the head and the disease caused by the under production of the biological neck (SCCHN), prostate cancer, pharyngeal cancer, rectal molecule. carcinoma, retinoblastoma, vaginal cancer, thyroid carci 0005. It is the object of the present invention to provide a noma, Schneeberger disease, esophageal cancer, spinalioms, compound for the prophylaxis and/or treatment of cancer, T-cell lymphoma (mycosis fungoides), thymoma, tube carci autoimmune diseases, fibrotic diseases, inflammatory dis noma, eye tumors, urethral cancer, urologic tumors, urothe eases, neurodegenerative diseases, infectious diseases, lung lial carcinoma, Vulva cancer, wart appearance, Soft tissue diseases, heart and vascular diseases and metabolic diseases. tumors, soft tissue sarcoma, Wilm's tumor, cervical carci 0006. The object of the present invention is solved by the noma and tongue cancer. teaching of the independent claims. Further advantageous 0009. The peptide of the present invention was tested features, aspects and details of the invention are evident from using the assays described in Examples 1-7, 9-17 for their the dependent claims, the description, and the examples of the effect as active therapeutic agents in the prophylaxis and/or present application. treatment of cancer, proliferative diseases, tumors and their metaStaSeS. DESCRIPTION OF THE INVENTION Infectious Disease 0007. The present invention relates to the use of the pep tide Thr-Lys-Pro-Arg-OH (Tuftsin), its use as a therapeutic in 0010. The immune system in higher vertebrates represents medicine and for the prophylaxis and/or treatment of cancer, the first line of defense against various antigens that can enter autoimmune diseases, fibrotic diseases, inflammatory dis the vertebrate body, including microorganisms such as bac eases, neurodegenerative diseases, infectious diseases, lung teria, fungi and viruses that are the causative agents of a diseases, heart and vascular diseases and metabolic diseases. variety of diseases. Also disclosed are pharmaceutical formulations preferably in 0011. Despite large immunization programs, viral infec form of a lyophilisate or liquid buffer solution or artificial tions, such as influenza virus, human immunodeficiency virus mother milk formulation containing the inventive peptide. (“HIV), herpes simplex virus (“HSV”, type 1 or 2), human The peptide is especially useful for prophylaxis and/or treat papilloma virus (“HPV, type 16 or 18), human cytomega US 2010/0210567 A1 Aug. 19, 2010

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 drug-resistant variants have been described. New classes of infection, onchocerciasis (river blindness), opisthorciasis antiviral agents designed to target particular viral proteins (Opisthorcis infection), parvovirus infection, plague, Pneu Such as influenza neuraminidase are being developed. How mocystis carinii pneumonia (PCP), polio, Q fever, rabies, ever, the ability of viruses to mutate the target proteins rep respiratory syncytial virus (RSV) Infection, rheumatic fever, resents an obstacle for effective treatment with molecules Rift Valley fever, river blindness (onchocerciasis), rotavirus which selectively inhibit the function of specific viral infection, roundworm infection, salmonellosis, salmonella polypeptides. Thus, there is need for new therapeutic strate enteritidis, Scabies, Shigellosis, shingles, sleeping sickness, gies to prevent and treat viral infections. Smallpox, Streptococcal Infection, tapeworm infection (Tae 0012. Additionally, there is a need for new therapies for nia infection), tetanus, toxic shock syndrome, tuberculosis, the prevention and treatment of bacterial infections, espe ulcers (peptic ulcer disease), Valley fever, Vibrio para cially bacterial infections caused by multiple drug resistant haemolyticus infection, Vibrio vulnificus infection, viral hem bacteria. Currently, bacterial infections are treated with vari orrhagic fever, warts, waterborne infectious diseases, West ous antibiotics. Although antibiotics have and can be effective Nile virus infection (West Nile encephalitis), whooping in the treatment of various bacterial infections, there are a cough, yellow fever. number of limitations to the effectiveness and safety of anti 0015. Another aspect of the present invention is directed to biotics. For example, some individuals have an allergic reac the use of the peptide for prophylaxis and/or treatment of tion to certain antibiotics and other individuals suffer from prion diseases. serious side effects. Moreover, continued use of antibiotics 0016 Prions are infectious agents which do not have a for the treatment of bacterial infections contributes to forma nucleic acid genome. It seems that a protein alone is the tion of antibiotic-resistant strains of bacteria. infectious agent. A prion has been defined as “small proteina 0013 Another aspect of the present invention is directed to ceous infectious particle which resists inactivation by proce the use of the peptide for prophylaxis and/or treatment of dures that modify nucleic acids”. The discovery that proteins infectious diseases including opportunistic infections. alone can transmit an infectious disease came as a consider 0014 Examples of infectious diseases are AIDS, alveolar able Surprise to the Scientific community. Prion diseases are hydatid disease (AHD, echinococcosis), amebiasis (Entam often called “transmissible spongiform encephalopathies”. oeba histolytica infection), Angiostrongylus infection, because of the post mortem appearance of the brain with large anisakiasis, anthrax, babesiosis (Babesia infection), Balan vacuoles in the cortex and cerebellum. Probably most mam tidium infection (balantidiasis), Baylisascaris infection (rac malian species develop these diseases. Prion diseases are a coon roundworm), bilharzia (Schistosomiasis), Blastocystis group of neurodegenerative disorders of humans and animals hominis infection (blastomycosis), boreliosis, botulism, and the prion diseases can manifest as sporadic, genetic or Brainerd diarrhea, brucellosis, bovine spongiform encephal infectious disorders. Examples of prion diseases acquired by opathy (BSE), candidiasis, capillariasis (Capillaria infec exogenous infection are bovine spongiform encephalitis tion), chronic fatigue syndrome (CFS), Chagas disease (BSE) of cattle and the new variant of Creutzfeld-Jakob dis (American trypanosomiasis), chickenpox (Varicella-Zoster ease (VCJD) caused by BSE as well as scrapie of animals. virus), Chlamydia pneumoniae infection, cholera, Examples of human prion diseases include kuru, sporadic Creutzfeldt-Jakob disease (CJD), clonorchiasis (Clonorchis Creutzfeldt-Jakob disease (sCJD), familial CJD (f(JD), infection), cutaneous larva migrans (CLM) (hookworm iatrogenic CJD (iCJD), Gerstmann-Sträussler-Scheinker infection), coccidioidomycosis, conjunctivitis, Coxsackievi (GSS) disease, fatal familial insomnia (FFI), and especially rus A16 (hand, foot and mouth disease), cryptococcosis, the new variant CJD (nvCJD or vCJD). Cryptosporidium infection (cryptosporidiosis), Culex mos 0017. The name “prion' is used to describe the causative quito (West Nile virus vector), cyclosporiasis (Cyclospora agents which underlie the transmissible spongiform encepha infection), cysticercosis (neurocysticercosis), Cytomegalovi lopathies. A prion is proposed to be a novel infectious particle rus infection, Dengue/Dengue fever, Dipylidium infection that differs from viruses and viroids. It is composed solely of (dog and cat flea tapeworm), Ebola virus hemorrhagic fever, one unique protein that resists most inactivation procedures encephalitis, Entamoeba coli infection, Entamoeba dispar Such as heat, radiation, and proteases. The latter characteristic infection, Entamoeba hartmanni infection, Entamoeba his has led to the term protease-resistant isoform of the prion tolytica infection (amebiasis), Entamoeba polecki infection, protein. The protease-resistant isoform has been proposed to enterobiasis (pinworm infection), enterovirus infection (non slowly catalyze the conversion of the normal prion protein polio), Epstein-Barr virus infection, Escherichia coli infec into the abnormal form. tion, foodborne infection, foot and mouth disease, fungal 0018. The term “isoform' in the context of prions means dermatitis, gastroenteritis, group A Streptococcal disease, two proteins with exactly the same amino acid sequence that group B streptococcal disease, Hansen's disease (leprosy), can fold into molecules with dramatically different tertiary Hantavirus pulmonary syndrome, head lice infestation (pe structures. The normal cellular isoform of the prion protein diculosis), Helicobacter pylori infection, hematologic dis (PrP) has a high C-helix content, a low f-sheet content, and ease, Hendra virus infection, hepatitis (HCV. HBV), herpes is sensitive to protease digestion. The abnormal, disease US 2010/0210567 A1 Aug. 19, 2010 causing isoform (PrP) has a lower C-helix content, a much higher B-sheet content, and is much more resistant to protease digestion. INCIDENCE: 140,000-320,000 infections/year in United States 0019. As used herein the term “prion diseases’ refers to PREVALENCE: Estimated 1-1.25 million chronically infected transmissible spongiform encephalopathies. Examples for Americans prion diseases comprise scrapie (sheep, goat), transmissible COSTS: Estimated $700 million (1991 dollars) year (medical mink encephalopathy (TME, mink), chronic wasting disease and work loss) (CWD; muledeer, deer, elk), bovine spongiform encephal opathy (BSE: cows, cattles), Creutzfeld-Jacob Disease 0025 Hepatitis D infection can only occur with a con comitant infection with Hepatitis B virus because the Hepa (CJD), variant CJD (VCJD), sporadic Creutzfeldt-Jakob dis titis D virus uses the Hepatitis B virus surface antigen to form ease (SCJD), familial CJD (f(JD), iatrogenic CJD (iCJD. a capsid. Co-infection with hepatitis D increases the risk of Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal liver cirrhosis and liver cancer. Polyarteritis nodosa is more familial insomnia (FFI), and kuru. Preferred are BSE, VCJD. common in people with hepatitis B infection. and CJD. 0026 Chronic carriers of the HBV have been defined as 0020. The peptide of the present invention was tested those who are HBV surface antigen positive for greater than using the assays described in Examples 1-7 for their effect as 6 months. Approximately 5-10% of those people who are active therapeutic agents in the prophylaxis and/or treatment infected with the virus will become carriers, an estimated of infectious diseases and disorders. 5-10% of those people infected each year will progress to chronic liver disease, cirrhosis and possibly liver cancer. Hepatitis B Virus (HBV) Infection About 5,000 people die in the United States each year related to HBV, 1,000 die of HBV-related liver cancer. The incuba 0021 Hepatitis is an inflammation of the liver that is most tion period of HBV usually lasts from 2 to 4 months, although often caused by infection with one offive viruses, hepatitis A. it may be very short (10 days) or extremely long (9 months). B, C, D or E. Hepatitis B virus infection may either be acute 0027. The tests, called assays, for detection of hepatitis B (self-limiting) or chronic (long-standing). Persons with self virus infection involve serum or blood tests that detect either limiting infection clear the infection spontaneously within viral antigens (proteins produced by the virus) or antibodies weeks to months. In cases, particularly in those related to produced by the host. hepatitis B and C, "chronic hepatitis” may result. Chronic 0028. The hepatitis B surface antigen (HBSAg) is most hepatitis occurs when the body is unable to completely clear frequently used to screen for the presence of this infection. It the virus even though the symptoms may not persist. is the first detectable viral antigen to appear during infection. However, early in an infection, this antigen may not be 0022 Children are less likely than adults to clear the infec present and it may be undetectable later in the infection as it tion. More than 95% of people who become infected as adults is being cleared by the host. The infectious virion contains an or older children will stage a full recovery and develop pro inner"core particle' enclosing viral genome. The icosahedral tective immunity to the virus. However, only 5% of newborns core particle is made of 180 or 240 copies of core protein, that acquire the infection from their mother at birth will clear alternatively known as hepatitis B core antigen, or HBcAg. the infection. Of those infected between the age of one to six, During this window in which the host remains infected but 70% will clear the infection. is successfully clearing the virus, IgM antibodies to the hepa 0023 Acute infection with hepatitis B virus is associated titis B core antigen (anti-HBc IgM) may be the only serologi with acute viral hepatitis—an illness that begins with general cal evidence of disease. ill-health, loss of appetite, nausea, vomiting, body aches, mild 0029. Shortly after the appearance of the HBS Ag, another fever, dark urine, and then progresses to development of antigen named as the hepatitis Be antigen (HBeAg) will jaundice. It has been noted that itchy skin has been an indi appear. Traditionally, the presence of HBeAg in a host's cation as a possible symptom of all hepatitis virus types. The serum is associated with much higher rates of viral replication illness lasts for a few weeks and then gradually improves in and enhanced infectivity; however, variants of the hepatitis B most affected people. A few patients may have more severe virus do not produce the 'e' antigen, so this rule does not liver disease (fulminant hepatic failure), and may die as a always hold true. During the natural course of an infection, result of it. The infection may be entirely asymptomatic and the HBeAg may be cleared, and antibodies to the ‘e’ antigen may go unrecognized. (anti-HBe) will arise immediately afterwards. This conver 0024 Continued presence of the virus over a number of sion is usually associated with a dramatic decline in viral years can lead to cirrhosis (scarring of the liver). This type of replication. infection dramatically increases the incidence of hepatocel 0030 Individuals who remain HBs.Ag positive for at least lular carcinoma (liver cancer). Chronic carriers should avoid six months are considered to be hepatitis B carriers. Carriers consuming alcohol as it increases their risk for cirrhosis and of the virus may have chronic hepatitis B, which would be liver cancer. It is estimated that approximately 350 million reflected by elevated serum alanine aminotransferase levels people worldwide are infected with chronic hepatitis B. HBV and inflammation of the liver, as revealed by biopsy. Carriers is transmitted through sexual contact, Vertical transmission who have seroconverted to HBeAg negative status, particu (mother to child at birth) or by coming into contact with larly those who acquired the infection as adults, have very contaminated blood. It is estimated that over 2 billion people little viral multiplication and hence may be at little risk of worldwide have been infected with hepatitis B virus. Of these long-term complications or of transmitting infection to oth 2 billion, approximately 350 million people have developed ers. Therefore, the most significant event indicating a chronic chronic HBV infection, putting them at high risk of develop course of hepatitis B is the absence of the HBS Ag/anti-HBs ing cirrhosis and liver cancer. seroconversion. If this phenomenon has not occurred within 6 US 2010/0210567 A1 Aug. 19, 2010

months after the onset of the disease, persistence of the HBV towards women. For example, in SLE the ratio of female to infection and the related clinical pictures (asymptomatic male patients is nine to one. In one particular case, Hashimo HBS Ag carrier, chronic hepatitis, cirrhosis, or hepatoma) to's disease in which the immune system attacks the thyroid have to be reckoned with. gland, the ratio is fifty to one. 0031) More recently, PCR tests have been developed to 0037. It has long been known that immune complex for detect and measure the amount of viral nucleic acid in clinical mation plays a role in the etiology and progression of autoim specimens. These tests are called viral loads and are used to mune disease. For example, inflammation in patients with assess a person's infection status and to monitor treatment. arthritis has long been considered to involve phagocytosis by Treatment of chronic infection is necessary to reduce the risk leukocytes of complexes of antigen, antibody and comple of cirrhosis and liver cancer. Chronically infected individuals ment-immune complexes. However, only now it is being rec with persistently elevated serumalanine aminotransferase, a ognized that inflammation caused by immune complexes in marker of liver damage, and HBV DNA levels are candidates the joints (arthritis), the kidneys (glomerulonephritis), and for therapy. blood vessels (vasculitis) is a major cause of morbidity in 0032. While monotherapy treatment with either Epivir autoimmune diseases. Increased immune complex formation HBV (lamivudine, 3TC) or Intron A (interferon-alfa) shows correlates with the presence of antibodies directed to self or some benefits for chronic hepatitis B. None of the available so-called autoantibodies, and the presence of the latter can drugs can clear the infection, but they can help stop the virus also contribute to tissue inflammation either as part of an from replicating, and prevent liver damage Such as cirrhosis immune complex or unbound to antigen (free antibody). In and liver cancer. Treatments include antiviral drugs such as Some autoimmune diseases, the presence of free autoanti lamivudine, adefovir and entecavir, telbivudine, and immune body contributes significantly to disease pathology. This has system modulators such as interferon alpha. However, some been clearly demonstrated for example in SLE (anti-DNA individuals are much more likely to respond than others and antibodies), immune thrombocytopenia (antibody response this might be because of the genotype of the infecting virus or directed to platelets), and to a lesser extent rheumatoid arthri the patient's heredity, and therefore there is a need for addi tis (IgG reactive rheumatoid factor). The important role of tional therapies. The virus is divided into four major serotypes immune complexes and free autoantibodies is further dem (adr, adw, ayr, ayw) based on antigenic epitopes present on its onstrated by the fact that successful treatment of certain envelope proteins, and into eight genotypes (A-H) according autoimmune diseases has been achieved by the removal of to overall nucleotide sequence variation of the genome. The immune complexes and free antibody by means of specific genotypes have a distinct geographical distribution and are immunoadsorption procedures. For example, the use of an used in tracing the evolution and transmission of the virus. apheresis procedure in which immune complexes and anti Differences between genotypes affect the disease severity, bodies are removed by passage of a patient’s blood through an course and likelihood of complications, and response to treat immunoaffinity column was approved by the U.S. FDA in ment. The treatment works by reducing the viral load, (the 1987 for immune thrombocytopenia (ITP) and in 1999 for amount of virus particles as measured in the blood), which in rheumatoid arthritis. However, currently there is no approved turn reduces viral replication in the liver. method for the treatment of autoimmune diseases which 0033 Infants born to mothers known to carry hepatitis B facilitates the elimination of immune complexes and autoan can be treated with antibodies to the hepatitis B virus (hepa tibodies by administration of a drug. titis B immune globulin or HBIg). When given with the vac 0038 Another aspect of the etiology and progression of cine within twelve hours of birth, the risk of acquiring hepa autoimmune disease is the role of proinflammatory cytokines. titis B is reduced 95%. This treatment allows a mother to Under normal circumstances, proinflammatory cytokines safely breastfeed her child. such as tumor necrosis factor C. (TNFC.) and interleukin-1 0034. The peptides 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. 0035. 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 0039 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 0036. 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. US 2010/0210567 A1 Aug. 19, 2010

0040. The interaction of leukocytes with the vessel endot 0050 Example of autoimmune diseases of the lung is helium to facilitate the extravasation into the tissue represents Goodpasture's syndrome. a key process of the body's defense mechanisms. Excessive 0051. An example of an autoimmune disease of the stom recruitment of leukocytes into the inflamed tissue in chronic ach is chronic atrophic (type A) gastritis. diseases like autoimmune disorders could be prevented by 0.052 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 0053 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 0054 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 0055. 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 0041) 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 0042 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 0056. 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. 0043. Examples of hematological autoimmune diseases are autoimmune hemolytic anemia, autoimmune neutrope Fibrotic Disease nia, Evans syndrome, inhibitor hemophilia, idiopathic throm 0057 Fibrosis or fibrosis associated disorder affects the bocytopenial purpura (ITP) and pernicious anemia. liver, epidermis, endodermis, muscle, tendon, cartilage, 0044 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, 0045 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 0046 Examples of autoimmune diseases of the ear, nose ment the fibrosis or fibrosis associated disorder is the result of and throat are chronic sensorineural hearing loss and morbus wound healing. Meniére. 0.058 Fibrosis is generally characterized by the pathologic 0047. 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 0048 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 0049. 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, 0.5 coronary infarcts, cere cirrhosis (PBC), and primary Sclerosing cholangitis. bral infarcts, myocardial fibrosis, musculoskeletal fibrosis, US 2010/0210567 A1 Aug. 19, 2010 post-Surgical adhesions, human kidney disease (e.g., vides protection against apoptosis. Thus, this well-known nephritic syndrome, Alport's syndrome, HIV associated fibrogenic cytokine is important both for the emergence of the nephropathy, polycystic kidney disease, Fabry's disease, dia myofibroblast and its survival against apoptotic stimuli. This betic nephropathy, chronic glomerulonephritis, nephritis is consistent with the critical importance of this cytokine in associated with systemic lupus, and the like), cutis keloid diverse models of fibrosis in various tissues. In view of these formation, progressive systemic sclerosis (PSS), primary properties, the persistence or prolonged Survival of the myo sclerosing cholangitis (PSC), liver fibrosis, liver cirrhosis, fibroblast may be the key to understanding why certain forms renal fibrosis, pulmonary fibrosis, cystic fibrosis, chronic of lung injury may result in progressive disease, terminating graft versus host disease, Scleroderma (local and systemic), Grave's opthalmopathy, diabetic retinopathy, glaucoma, Pey in end stage disease. ronie's disease, penis fibrosis, urethrostenosis after a test 0062 Although pulmonary fibrosis has diverse etiologies, using a cystoscope, inner accretion after Surgery, Scarring, there is a common feature characteristic of this process, myelofibrosis, idiopathic retroperitoneal fibrosis, peritoneal namely, the abnormal deposition of extracellular matrix that fibrosis from a known etiology, drug induced ergotism, fibro effaces the normal lung tissue architecture. A key cellular sis incident to benign or malignant cancer, fibrosis incident to Source of this matrix is the mesenchymal cell population that microbial infection (e.g., viral, bacterial, parasitic, fungal, occupies much of the fibrotic lesion during the active period etc.), Alzheimer's disease, fibrosis incident to inflammatory offibrosis. This population is heterogeneous with respect to a bowel disease (including stricture formation in Crohn's dis number of key phenotypes. One of these phenotypes is the ease and microscopic colitis), fibrosis induced by chemical or myofibroblast, which is commonly identified by its expres environmental insult (e.g., cancer chemotherapy, pesticides, sion in C-Smooth muscle actin and by features that are inter radiation/cancer radiotherapy), and the like. mediate between the bona fide smooth muscle cell and the 0059 Diseases associated with fibrosis include lupus, fibroblast. The de novo appearance of myofibroblasts at sites graft versus host disease, Scleroderma, systemic sclerosis, of wound healing and tissue repair/fibrosis is associated with Scleroderma-like disorders, sine Scleroderma, calcinosis, the period of active fibrosis and is considered to be involved in Raynaud's esophageal dysfunction, Sclerodactyl), telang wound contraction. Furthermore, the localization of myofi iectasiae, hypersensitivity pneumonitis, collagen vascular broblasts at sites undergoing active extracellular matrix depo disease, asthma, pulmonary arterial hypertension, glomeru sition Suggests an important role for these cells in the genesis lonephritis, chronic obstructive pulmonary disease, fibrosis of the fibrotic lesion. following myocardial infarction, central nervous system fibrosis following a stroke or neuro-degenerative diseases Increased TGF-B Family Levels in Fibrotic Diseases (e.g. Alzheimer's disease), proliferative vitreoretinopathy 0063. The transforming growth factor-B (TGF-B) family (PVR) and arthritis, silicosis, asbestos induced pulmonary of proteins has the most potent stimulatory effect on extra fibrosis, acute lung injury and acute respiratory distress Syn cellular matrix deposition of any cytokines so far examined. drome (including bacterial pneumonia induced, trauma In animal models of pulmonary fibrosis enhanced TGF-B induced, viral pneumonia induced, tuberculosis, ventilator gene expression is temporally and spatially related to induced, non-pulmonary sepsis induced, and aspiration increased collagen gene expression and protein deposition. induced). TGF-B antibodies reduce collagen deposition in murine bleomycin-induced lung fibrosis and human fibrotic lung tis Increased Number of Activated Myofibroblasts in Fibrotic Sue shows enhanced TGF-B gene and protein expression. Diseases Several lines of evidence suggest that TGF-B is a central 0060. The emergence and disappearance of the myofibro regulator of pulmonary fibrosis. Several animal models over blast appears to correlate with the initiation of active fibrosis expressing TGF-B showed extensive progressive fibrosis but and its resolution, respectively. In addition, the myofibroblast limited inflammation, indicating that TGF-B may play a pre has many phenotypic features, which embody much of the dominant role in the progression of pulmonary fibrosis. pathologic alterations in fibrotic tissue, e.g. lung tissue. These Therapeutic efforts are therefore focusing on inhibition of features would seem to argue for an important role for the TGF-B activity, for instance by anti-TGF-31-antibodies, or myofibroblast in the pathogenesis of fibrosis, e.g. lung fibro modulators of TGF-31 such as pirfenidone. Pirfenidone sis. Furthermore, the persistence of the myofibroblast may inhibits TGF-B1 gene expression in vivo resulting in inhibi herald progressive disease, and, conversely, its disappearance tion of TGF-31-mediated collagen synthesis and appears to may be an indicator of resolution. This in turn suggests that slow progression of IPF in patients. Other novel, promising future therapeutic strategies targeting the myofibroblast antifibrotic agents include relaxin (inhibits TGF-3-mediated would be productive. overexpression of collagen and increases collagenases), 0061 Patients usually exhibit evidence of active fibrosis Suramin (inhibits growth factors), prostaglandin E2 (inhibits with increased numbers of activated fibroblasts, many of collagen production) and lovastatin (blocks formation of which have the phenotypic characteristics of myofibroblasts. granulation tissue by induction of fibroblast apoptosis). At these sites, increased amounts of extracellular matrix 0064 Diseases involving the lung associated with deposition are evident with effacement of the normal alveolar increased levels of TGF-B include chronic lung disease of architecture. Animal model studies show the myofibroblast to prematurity, idiopathic pulmonary fibrosis, rapid progressive be the primary Source of type I collagen gene expression in pulmonary fibrosis, giant-cell interstitial pneumonia, acute active fibrotic sites. In vitro studies show differentiation of rejection after lung transplantation, cytomegalovirus pneu these cells from fibroblasts under the influence of certain monitis after lung transplantation, bronchiolitis obliterans, cytokines but indicate their susceptibility to nitric oxide asbestosis, coal worker's pneumoconiosis, silicosis, histiocy mediated apoptosis. In addition to promoting myofibroblast tosis, sarcoidosis, eosinophilic granuloma, Scleroderma, sys differentiation, transforming growth factor-f1 (TGF-31) pro temic lupus erythematosus, lymphangioleiomyomatosis, US 2010/0210567 A1 Aug. 19, 2010

central fibrosis inpulmonary adenocarcinoma, cystic fibrosis, lavage (BAL) fluid. Indeed, a synthetic inhibitor of MMP, chronic obstructive lung disease, and asthma. Batimastat, has been shown to significantly reduce bleomy cin-induced lung fibrosis, again pointing to the importance of Increased TNF-C. Levels in Fibrotic Diseases MMPs in the development of this fibrotic disease in the lung. 0065. An important role of tumor necrosis factor-O. (TNF A number of studies have shown that the actions of MMPs can C.) in interstitial fibrosis has been established using transgenic result in the release of growth factors and cytokines. These mice, which either overexpress or display a deficiency of this profibrotic factors require proteolytic processing for their cytokine. Mice transgenically modified to overexpress activation or release from extracellular matrix or carrier pro TNF-C. develop lung fibrosis. In contrast, mice null for teins before they can exert their activity. In fact, the pro TNF-C. show marked resistance to bleomycin induced fibro teolytic activity processing of several key factors involved in sis. TNF-C. can stimulate fibroblast replication and collagen the pathogenesis of pulmonary fibrosis Such as insulin-like synthesis in vitro, and pulmonary TNF-C. gene expression growth factor (IGF). TGF-B and TNF-C. occur through the rises after administration of bleomycin in mice. Soluble actions of MMPs, thereby activating or releasing them from TNF-C. receptors reduce lung fibrosis in murine models and inhibitory protein-protein interactions. For example, IGFs in pulmonary overexpression of TNF-C. in transgenic mice is vivo are sequestered by six high affinity IGF binding proteins characterized by lung fibrosis. In patients with CFA or asbes (IGFBPs 1-6), preventing their ability to interact with IGF tosis, bronchoalveolar lavage fluid-derived macrophages receptors. Studies examining adults and children IPF and release increased amounts of TNF-C. compared with controls. interstitial lung disease show that beside IPF, IGFBP-3 and 0066 Increased TNF-C. may induce fibrosis or fibrosis IFPB-2 levels are increased in IPF BAL fluid. MMPs have associated conditions affecting any tissue including, for recently been shown to regulate the cleavage of IGF binding example, fibrosis of an internal organ, a cutaneous or dermal proteins, thereby liberating the complexed ligand to affect fibrosing disorder, and fibrotic conditions of the eye. Fibrosis IGF actions in target cells. Observations have also shown that of internal organs (e.g., liver, lung, kidney, heart blood ves the gelatinases, MMP-9 and MMP-2 may be involved in sels, gastrointestinal tract) occurs in disorders such as pulmo proteolytic activation of latent TGF-B complexes. Further nary fibrosis, idiopathic fibrosis, autoimmune fibrosis, more, the MMP inhibitor Batimastat reduces MMP-9 activity myelofibrosis, liver cirrhosis, veno-occlusive disease, mesan in BAL fluid, which was associated with decreased amount of gial proliferative glomerulonephritis, crescentic glomerulo TGF-B and TNF-C. nephritis, diabetic nephropathy, renal interstitial fibrosis, 0068 Pulmonary fibrosis can be an all too common con renal fibrosis in Subjects receiving cyclosporin, allograft sequence of an acute inflammatory response of the lung to a rejection, HTV associated nephropathy. Other fibrosis-asso host of inciting events. Chronic lung injury due to fibrotic ciated disorders include systemic sclerosis, eosinophilia-my changes can result from an identifiable inflammatory event or algia syndrome, and fibrosis-associated CNS disorders such an insidious, unknown event. The inflammatory process can as intraocular fibrosis. Dermal fibrosing disorders include, for include infiltration of various inflammatory cell types, such as example, Scleroderma, morphea, keloids, hypertrophic scars, neutrophils and macrophages, the secretion of inflammatory familial cutaneous collagenoma, and connective tissue nevi cytokines and chemokines and the Secretion of matrix remod of the collagen type. Fibrotic conditions of the eye include eling proteinases. conditions such as diabetic retinopathy, post-Surgical scarring (for example, after glaucoma filtering Surgery and after Increased CCL 18 Levels in Fibrotic Diseases crossed-eyes (strabismus) Surgery), and proliferative vitreo retinopathy. Additional fibrotic conditions that may be treated 0069. The expression and regulation of cysteine-cysteine by the methods of the present invention may result, for (CC) chemokine ligand 18 (CCL18), a marker of alternative example, from rheumatoid arthritis, diseases associated with activation, by human alveolar macrophages (AMs) is prolonged joint pain and deteriorated joints; progressive sys increased in patients with pulmonary fibrosis and correlates temic sclerosis, polymyositis, dermatomyositis, eosinophilic negatively with pulmonary function test parameters. Thus, fasciitis, morphea, Raynaud's syndrome, and nasal polyposis. CCL 18 is an ideal diagnostic marker for pulmonary fibrosis. 0070 The peptide of the present invention was tested Increased Matrix Metalloproteases Levels in Fibrotic Dis using the assays described in Examples 14-15 for their effect CaSS as active therapeutic agents in the prophylaxis and/or treat ment of fibrotic diseases and disorders. 0067. The abnormal extracellular matrix (ECM) remodel ing observed in the lungs of patients with interstitial pulmo Inflammatory Disease nary fibrosis (IPF) is due, at least in part, to an imbalance between matrix metalloproteases (MMPs) and tissue inhibi 0071 Inflammation is the final common pathway of vari tor of metalloproteinases (TIMPs). Normal lung fibroblasts ous insults, such as infection, trauma, and allergies to the do not make MMP-9 in vitro, whereas fibroblasts from IPF human body. It is characterized by activation of the immune lungs strongly express MMP-9. In addition, fibroblasts from system with recruitment of inflammatory cells, production of patients with IPF express increased levels of all TIMPs. In this pro-inflammatory cells and production of pro-inflammatory setting, TIMPs may play a role in apoptosis in some cell cytokines. Most inflammatory diseases and disorders are populations. In vitro studies of alveolar macrophages characterized by abnormal accumulation of inflammatory obtained from untreated patients with idiopathic pulmonary cells including monocytes/macrophages, granulocytes, fibrosis showed marked increase in MMP-9 secretion com plasma cells, lymphocytes and platelets. Along with tissue pared to macrophages collected from healthy individuals. In endothelial cells and fibroblasts, these inflammatory cells animals models of bleomycin-induced pulmonary fibrosis release a complex array of lipids, growth factors, cytokines MMPs have been shown to be elevated in bronchoalveolar and destructive enzymes that cause local tissue damage. US 2010/0210567 A1 Aug. 19, 2010

0072. One form of inflammatory response is neutrophilic toses. Immunoinflammatory disorders result in the inflammation which is characterized by infiltration of the destruction of healthy tissue by an inflammatory process, inflamed tissue by neutrophil polymorphonuclear leukocytes dysregulation of the immune system, and unwanted prolif (PMN), which are a major component of the host defense. eration of cells. Examples of immunoinflammatory disorders Tissue infection by extracellular bacteria represents the pro are acne Vulgaris; acute respiratory distress syndrome; Addi totype of this inflammatory response. On the other hand, son's disease; allergic rhinitis; allergic intraocular inflamma various non-infectious diseases are characterized by tory diseases, antineutrophil cytoplasmic antibody (ANCA)- extravascular recruitment of neutrophils. This group of associated Small-vessel vasculitis; ankylosing spondylitis; 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 0073 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; 0074 TNF-C. has several biologic activities that are impor uveitis; vasculitis; and Wegener's granulomatosis. tant in homeostasis as well as in pathophysiological condi 0076. 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 0075. 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 US 2010/0210567 A1 Aug. 19, 2010

drome), bowel-associated dermatosis-arthritis syndrome, induced by UV radiation (sun rays and similar UV rheumatoid neutrophilic dermatosis, neutrophilic eccrine Sources):—erythema, pain, Scaling, Swelling, tender hidradenitis, neutrophilic dermatosis of the dorsal hands, bal neSS, anitis circumscripta plasmacellularis, balanoposthitis, Beh 0090 inflammatory bowel disease, such as Crohn's dis cet's disease, erythema annulare centrifugum, erythema dys ease, ulcerative colitis: pain, diarrhea, constipation, chromicum perstans, erythema multiforme, granuloma rectal bleeding, fever, arthritis; annulare, hand dermatitis, lichen nitidus, lichen planus, 0.091 asthma:—shortness of breath, wheezing: lichen Sclerosus et atrophicus, lichen simplex chronicus, 0092 other allergy disorders, such as allergic rhini lichen spinulosus, nummular dermatitis, pyoderma gan tis:—Sneezing, itching, runny nose grenosum, sarcoidosis, Subcorneal pustular dermatosis, urti 0093 conditions associated with acute trauma such as caria, and transient acantholytic dermatosis. cerebral injury following stroke-sensory loss, motor 0077. By “proliferative skin disease' is meant a benign or loss, cognitive loss; malignant disease that is characterized by accelerated cell 0094 heart tissue injury due to myocardial ischemia:— division in the epidermis or dermis. Examples of proliferative pain, shortness of breath; skin diseases are psoriasis, atopic dermatitis, nonspecific der 0.095 lung injury such as that which occurs in adult matitis, primary irritant contact dermatitis, allergic contact respiratory distress syndrome:—shortness of breath, dermatitis, basal and squamous cell carcinomas of the skin, hyperventilation, decreased oxygenation, pulmonary lamellar ichthyosis, epidermolytic hyperkeratosis, premalig infiltrates; nant keratosis, acne, and seborrheic dermatitis. As will be 0096 inflammation accompanying infection, such as appreciated by one skilled in the art, a particular disease, sepsis, septic shock, toxic shock syndrome:—fever, res disorder, or condition may be characterized as being both a piratory failure, tachycardia, hypotension, leukocytosis; proliferative skin disease and an inflammatory dermatosis. 0097 other inflammatory conditions associated with An example of Such a disease is psoriasis. particular organs or tissues, such as: 0078 Symptoms and signs of inflammation associated (i) nephritis (e.g., glomeralonephritis):—oliguria, abnormal with specific conditions include: urinalysis; 0079 rheumatoid arthritis: pain, swelling, warmth (ii) inflamed appendix:—fever, pain, tenderness, leukocyto and tenderness of the involved joints; generalized and S1S, morning stiffness; (iii) gout:- pain, tenderness, Swelling and erythema of the 0080 insulin-dependent diabetes mellitus-insulitis; this involved joint, elevated serum and/or urinary uric acid: condition can lead to a variety of complications with an (iv) inflamed gallbladder:—abdominal pain and tenderness, inflammatory component, including:—retinopathy, fever, nausea, leukocytosis; neuropathy, nephropathy; coronary artery disease, (V) congestive heart failure:—shortness of breath, rales, peripheral vascular disease, and cerebrovascular dis peripheral edema; ease, (vi) Type II diabetes:—end organ complications including I0081 autoimmune thyroiditis: weakness, constipa cardiovascular, ocular, renal, and peripheral vascular disease; tion, shortness of breath, puffiness of the face, hands and (vii) lung (pulmonary) fibrosis:—hyperventilation, shortness feet, peripheral edema, bradycardia; of breath, decreased oxygenation; I0082 multiple sclerosis:—spasticity, blurry vision, ver (viii) vascular disease, Such as atherosclerosis and resteno tigo, limb weakness, paresthesias; sis: pain, loss of sensation, diminished pulses, loss of func tion; and I0083 uveoretinitis:—decreased night vision, loss of (ix) alloimmunity leading to transplant rejection: pain, ten peripheral vision; derness, fever. 0084 lupus erythematosus:- joint pain, rash, photo 0098. 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 I0085 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 0099. The peptide of the present invention was tested trointestinal dysfunction, restrictive lung disease; peri using the assays described in Examples 1-7, 9-17 for their carditis; renal failure; effect as active therapeutic agents in the prophylaxis and/or I0086 other arthritic conditions having an inflammatory treatment of inflammatory diseases and disorders. component such as rheumatoid spondylitis, osteoarthri tis, septic arthritis and polyarthritis:—fever, pain, Swell Neurodegenerative Disease ing, tenderness; 0100. The present invention also relates generally to the I0087 other inflammatory brain disorders, such as men fields of neurology and psychiatry and to methods of protect ingitis, Alzheimer's disease, AIDS dementia encephali ing the cells of a mammalian central nervous system from tis: photophobia, cognitive dysfunction, memory loss; damage or injury. I0088 other inflammatory eye inflammations, such as 0101 Injuries or trauma of various kinds to the central retinitis:—decreased visual acuity; nervous system (CNS) or the peripheral nervous system I0089 inflammatory skin disorders, such as, eczema, (PNS) can produce profound and long-lasting neurological other dermatites (e.g., atopic, contact), psoriasis, burns and/or psychiatric symptoms and disorders. One form that US 2010/0210567 A1 Aug. 19, 2010

this can take is the progressive death of neurons or other cells kinson’s-dementia complex of Guam, Subacute Sclerosing of the central nervous system (CNS), i.e., neurodegeneration panencephalitis, Huntington's disease, Parkinson's disease, or neuronal degeneration. Synucleinopathies (including multiple system atrophy), pri 0102 Neuronal degeneration as a result of, for example: mary progressive aphasia, striatonigral degeneration, Alzheimer's disease, multiple Sclerosis, cerebral-vascular Machado-Joseph disease or spinocerebellar ataxia type 3 and accidents (CVAS)/stroke, traumatic brain injury, spinal cord olivopontocerebellar degenerations, bulbar and pseudobulbar injuries, degeneration of the optic nerve, e.g., ischemic optic palsy, spinal and spinobulbar muscular atrophy (Kennedy's neuropathy or retinal degeneration and other central nervous disease), primary lateral Sclerosis, familial spastic paraplegia, system disorders is an enormous medical and public health Werdnig-Hoffmann disease, Kugelberg-Welander disease, problem by virtue of both its high incidence and the frequency Tay-Sach's disease, Sandhoff disease, familial spastic dis of long-term sequelae. Animal studies and clinical trials have ease, Wohlfart-Kugelberg-Welander disease, spastic para shown that amino acid transmitters (especially glutamate), paresis, progressive multifocal leukoencephalopathy, famil oxidative stress and inflammatory reactions contribute ial dysautonomia (Riley-Day Syndrome) or prion diseases strongly to cell death in these conditions. Upon injury or upon (including, but not limited to Creutzfeld-Jakob disease, Ger ischemic insult, damaged neurons release massive amounts stmann-Strussler-Scheinker disease, Kuru disease or fatal of the neurotransmitter glutamate, which is excitotoxic to the familial insomnia). Surrounding neurons. Glutamate is a negatively charged 0106. In addition, trauma and progressive injury to the amino acid that is an excitatory synaptic transmitter in the nervous system can take place in various psychiatric disor mammalian nervous system. Although the concentration of ders, including but not limited to, progressive, deteriorating glutamate can reach the millimolar range in nerve terminals forms of bipolar disorder or schizoaffective disorder or its extracellular concentration is maintained at a low level to Schizophrenia, impulse control disorders, obsessive compul prevent neurotoxicity. It has been noted that glutamate can be sive disorder (OCD), behavioral changes in temporal lobe toxic to neurons if presented at a high concentration. The term epilepsy and personality disorders. “excitotoxicity' has been used to describe the cytotoxic effect 0107. In one preferred embodiment the compounds of the that glutamate (and other Such excitatory amino acids) can invention would be used to provide neuroprotection in disor have on neurons when applied at high dosages. ders involving trauma and progressive injury to the nervous 0103 Patients with injury or damage of any kind to the system in various psychiatric disorders. These disorders central (CNS) or peripheral (PNS) nervous system including would be selected from the group consisting of Schizoaffec the retina may benefit from neuroprotective methods. This tive disorder, schizophrenia, impulse control disorders, nervous system injury may take the form of anabrupt insult or obsessive compulsive disorder (OCD) and personality disor an acute injury to the nervous system as in, for example, acute ders. neurodegenerative disorders including, but not limited to: 0108. 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 0109) Other disorders associated with neuronal injury drome). include, but are not limited to, disorders associated with 0104. 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 0105 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). US 2010/0210567 A1 Aug. 19, 2010

0110. Further indications are cognitive disorders. The expressive language disorder, phonological disorder, mixed term “cognitive disorder shall refer to anxiety disorders, receptive-expressive language disorder, Stuttering, pervasive delirium, dementia, amnestic disorders, dissociative disor developmental disorders, Asperger's disorder, autistic disor ders, eating disorders, mood disorders, Schizophrenia, psy der, childhood disintegrative disorder, Rett's disorder, perva chotic disorders, sexual and gender identity disorders, sleep sive developmental disorder, attention-deficit/hyperactivity disorders, Somatoform disorders, acute stress disorder, obses disorder (ADHD), conduct disorder, oppositional defiant dis sive-compulsive disorder, panic disorder, posttraumatic order, feeding disorder of infancy or early childhood, pica, stress disorder, specific phobia, Social phobia, Substance rumination disorder, tic disorders, chronic motor or vocal tic withdrawal delirium, Alzheimer's disease, Creutzfeldt-Jakob disorder, Tourette's syndrome, elimination disorders, enco disease, head trauma, Huntington's disease, HIV disease, presis, enuresis, selective mutism, separation anxiety disor Parkinson's disease, Pick's disease, learning disorders, motor der, reactive attachment disorder of infancy or early child skills disorders, developmental coordination disorder, com hood, Stereotypic movement disorder. munication disorders, phonological disorder, pervasive 0113. Examples for substance-related disorders are: alco developmental disorders, Asperger's disorder, autistic disor hol related disorders, amphetamine related disorders, caf der, childhood disintegrative disorder, Rett's disorder, perva feine related disorders, cannabis related disorders, cocaine sive developmental disorder, attention-deficit/hyperactivity related disorders, hallucinogen related disorders, inhalant disorder (ADHD), conduct disorder, oppositional defiant dis related disorders, nicotine related disorders, opioid related order, pica, rumination disorder, tic disorders, chronic motor disorders, psychotic disorder, psychotic disorder, phencycli or vocal tic disorder, Tourette's disorder, elimination disor dine-related disorder, abuse, persisting amnestic disorder, ders, encopresis, enuresis, selective mutism, separation anxi anxiety disorder, persisting dementia, dependence, intoxica ety disorder, dissociative amnesia, depersonalization disor tion, intoxication delirium, mood disorder, psychotic disor der, dissociative fugue, dissociative identity disorder, der, withdrawal, withdrawal delirium, sexual dysfunction, anorexia nervosa, bulimia nervosa, bipolar disorders, Schizo sleep disorder. phreniform disorder, schizoaffective disorder, delusional dis 0114. The term “neuroprotection” as used herein shall order, psychotic disorder, shared psychotic disorder, delu mean: inhibiting, preventing, ameliorating or reducing the sions, hallucinations, Substance-induced psychotic disorder, severity of the dysfunction, degeneration or death of nerve orgasmic disorders, sexual pain disorders, dyspareunia, cells, axons or their supporting cells in the central or periph vaginismus, sexual dysfunction, paraphilias, dyssomnias, eral nervous system of a mammal, including a human. This breathing-related sleep disorder, circadian rhythm sleep dis includes the treatment or prophylaxis of a neurodegenerative order, hypersomnia, insomnia, narcolepsy, dyssomnia, para disease; protection against excitotoxicity or ameliorating the Somnias, nightmare disorder, sleep terror disorder, sleep cytotoxic effect of a compound (for example, a excitatory walking disorder, parasomnia, body dysmorphic disorder, amino acid Such as glutamate; a toxin; or a prophylactic or conversion disorder, hypochondriasis, pain disorder, Somati therapeutic compound that exerts an immediate or delayed Zation disorder, alcohol related disorders, amphetamine cytotoxic side effect including but not limited to the immedi related disorders, caffeine related disorders, cannabis related ate or delayed induction of apoptosis) in a patient in need disorders, cocaine related disorders, hallucinogen related dis thereof. orders, inhalant related disorders, nicotine related disorders, 0115 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 0111. 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 0116. 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), 0117. 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 0112 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 US 2010/0210567 A1 Aug. 19, 2010

of some known predisposition either biochemical or genetic neuronal damage, as the latter term is used herein, may be or the finding of a verified biomarker of one or more of these used in the methods of this invention for determining the need disorders. for treatment with the compounds and methods of this inven 0118. Thus, in some embodiments, the methods and com tion. positions of the present invention are directed toward neuro I0123. A determination that a subject has, or may be at risk protection in a subject who is at risk of developing neuronal for developing, neuronal damage would also include, for damage but who has not yet developed clinical evidence. This patient may simply be at “greater risk” as determined by the example, a medical evaluation that includes a thorough his recognition of any factor in a Subjects, or their families, tory, a physical examination, and a series of relevant bloods medical history, physical exam or testing that is indicative of tests. It can also include an electroencephalogram (EEG), CT, a greater than average risk for developing neuronal damage. MRI or PET scan. A determination of an increased risk of Therefore, this determination that a patient may be at a developing neuronal damage or injury may also be made by “greater risk” by any available means can be used to deter means of genetic testing, including gene expression profiling mine whether the patient should be treated with the methods or proteomic techniques. For psychiatric disorders that may of the present invention. be stabilized or improved by a neuroprotective drug, e.g., 0119. Accordingly, in an exemplary embodiment, subjects bipolar disorder, schizoaffective disorder, schizophrenia, who may benefit from treatment by the methods and peptide impulse control disorders, etc. the above tests may also of this invention can be identified using accepted Screening include a present state exam and a detailed history of the methods to determine risk factors for neuronal damage. These course of the patients symptoms Such as mood disorder Symp screening methods include, for example, conventional work toms and psychotic symptoms over time and in relation to ups to determine risk factors including but not limited to: for other treatments the patient may have received over time, e.g., example, head trauma, either closed or penetrating, CNS a life chart. These and other specialized and routine methods infections, bacterial or viral, cerebrovascular disease includ allow the clinician to select patients in need of therapy using ing but not limited to stroke, brain tumors, brain edema, the methods and formulations of this invention. In some cysticercosis, porphyria, metabolic encephalopathy, drug embodiments of the present invention peptide suitable for use withdrawal including but not limited to sedative-hypnotic or in the practice of this invention will be administered either alcohol withdrawal, abnormal perinatal history including singly or concomitantly with at least one or more other com anoxia at birth or birth injury of any kind, cerebral palsy, pounds ortherapeutic agents, e.g., with other neuroprotective learning disabilities, hyperactivity, history of febrile convul drugs or antiepileptic drugs, anticonvulsant drugs. In these sions as a child, history of status epilepticus, family history of epilepsy or any seizure related disorder, inflammatory disease embodiments, the present invention provides methods to treat of the brain including lupis, drug intoxication either director or prevent neuronal injury in a patient. The method includes by placental transfer, including but not limited to cocaine the step of administering to a patient in need of treatment, an poisoning, parental consanguinity, and treatment with medi effective amount of one of the peptide disclosed herein in cations that are toxic to the nervous system including psycho combination with an effective amount of one or more other tropic medications. compounds or therapeutic agents that have the ability to pro 0120. The determination of which patients may benefit vide neuroprotection or to treat or prevent seizures or epilep from treatment with a neuroprotective drug in patients who togenesis or the ability to augment the neuroprotective effects have no clinical signs or symptoms may be based on a variety of the compounds of the invention. of “surrogate markers' or “biomarkers’. 0.124. As used herein the term “combination administra 0121. As used herein, the terms “surrogate marker” and tion of a compound, therapeutic agent or known drug with “biomarker are used interchangeably and refer to any ana the peptide of the present invention means administration of tomical, biochemical, structural, electrical, genetic or chemi the drug and the one or more compounds at Such time that cal indicator or marker that can be reliably correlated with the both the known drug and the peptide will have a therapeutic present existence or future development of neuronal damage. effect. In some cases this therapeutic effect will be synergis In some instances, brain-imaging techniques, such as com tic. Such concomitant administration can involve concurrent puter tomography (CT), magnetic resonance imaging (MRI) (i.e. at the same time), prior, or Subsequent administration of or positron emission tomography (PET), can be used to deter the drug with respect to the administration of the peptide of mine whether a Subject is at risk for neuronal damage. Suit the present invention. A person of ordinary skill in the art able biomarkers for the methods of this invention include, but would have no difficulty determining the appropriate timing, are not limited to: the determination by MRI, CT or other sequence and dosages of administration for particular drugs imaging techniques, of Sclerosis, atrophy or Volume loss in and peptides of the present invention. the hippocampus or overt mesial temporal sclerosis (MTS) or 0.125. The said one or more other compounds or therapeu similar relevant anatomical pathology; the detection in the tic agents may be selected from compounds that have one or patient's blood, serum or tissues of a molecular species Such more of the following properties: antioxidant activity; as a protein or other biochemical biomarker, e.g., elevated NMDA receptor antagonist activity, augmentation of endog levels of ciliary neurotrophic factor (CNTF) or elevated enous GABA inhibition: NO synthase inhibitor activity; iron serum levels of a neuronal degradation product; or other binding ability, e.g., an iron chelator, calcium binding ability, evidence from Surrogate markers or biomarkers that the e.g., a Ca (II) chelator; Zinc binding ability, e.g., a Zn (II) patient is in need of treatment with a neuroprotective drug. chelator; the ability to effectively block sodium or calcium 0122. It is expected that many more such biomarkers uti ion channels, or to open potassium or chloride ion channels in lizing a wide variety of detection techniques will be devel the CNS of a patient. oped in the future. It is intended that any such marker or 0.126 The peptide of the present invention was tested indicator of the existence or possible future development of using the assays described in Examples 1-7, 9-17 for their US 2010/0210567 A1 Aug. 19, 2010 effect as active therapeutic agents in the prophylaxis and/or I0131 One of the more clinically significant forms of PVD treatment of neurodegenerative diseases and disorders. is peripheral artery disease (PAD). PAD is often treated by angioplasty and implantation of a stent or by artery bypass Heart and Vascular Disease Surgery. Clinical presentation depends on the location of the 0127 Heart disease is a general term used to describe occluded vessel. For example, narrowing of the artery that many different heart conditions. For example, coronary artery Supplies blood to the intestine can result in severe postpran disease, which is the most common heart disease, is charac dial pain in the lower abdomen resulting from the inability of terized by constriction or narrowing of the arteries Supplying the occluded vessel to meet the increased oxygen demand the heart with oxygen-rich blood, and can lead to myocardial arising from digestive and absorptive processes. In severe infarction, which is the death of a portion of the heart muscle. forms the ischemia can lead to intestinal necrosis. Similarly, Heart failure is a condition resulting from the inability of the PAD in the leg can lead to intermittent pain, usually in the heart to pump an adequate amount of blood through the body. calf, that comes and goes with activity. This disorder is known Heart failure is not a sudden, abrupt stop of heart activity but, as intermittent claudication (IC) and can progress to persis rather, typically develops slowly over many years, as the heart tent pain while resting, ischemic ulceration, and even ampu gradually loses its ability to pump blood efficiently. Risk tation. factors for heart failure include coronary artery disease, hypertension, valvular heart disease, cardiomyopathy, dis I0132) Peripheral vascular disease is also manifested in ease of the heart muscle, obesity, diabetes, and/or a family atherosclerotic stenosis of the renal artery, which can lead to history of heart failure. renal ischemia and kidney dysfunction. 0128. Examples of cardiovascular diseases and disorders 0133. One disease in which vascular diseases and their are: aneurysm, stable angina, unstable angina, angina pecto complications are very common is diabetes mellitus. Diabe ris, angioneurotic edema, aortic valve Stenosis, aortic aneu tes mellitus causes a variety of physiological and anatomical rysm, arrhythmia, arrhythmogenic right ventricular dyspla irregularities, the most prominent of which is the inability of sia, arteriosclerosis, arteriovenous malformations, atrial the body to utilize glucose normally, which results in hyper fibrillation, Behcet syndrome, bradycardia, cardiac tampon glycemia. Chronic diabetes can lead to complications of the ade, cardiomegaly, congestive cardiomyopathy, hypertrophic vascular system which include atherosclerosis, abnormalities cardiomyopathy, restrictive cardiomyopathy, carotid Steno involving large and medium size blood vessels (macroangi sis, cerebral hemorrhage, Churg-Strauss syndrome, diabetes, opathy) and abnormalities involving Small blood vessels (mi Ebstein's Anomaly, Eisenmenger complex, cholesterol croangiopathy) such as arterioles and capillaries. embolism, bacterial endocarditis, fibromuscular dysplasia, congenital heart defects, heart diseases, congestive heart fail 0.134 Patients with diabetes mellitus are at increased risk ure, heart Valve diseases, heart attack, epidural hematoma, of developing one or more foot ulcers as a result of established hematoma, Subdural, Hippel-Lindau disease, hyperemia, long-term complications of the disease, which include hypertension, pulmonary hypertension, cardiac hypertrophy, impaired nerve function (neuropathy) and/or ischemia. Local left ventricular hypertrophy, right ventricular hypertrophy, tissue ischemia is a key contributing factor to diabetic foot hypoplastic left heart syndrome, hypotension, intermittent ulceration. claudication, ischemic heart disease, Klippel-Trenaunay-We I0135) In addition to large vessel disease, patients with ber syndrome, lateral medullary syndrome, long QT syn diabetes suffer further threat to their skin perfusion in at least drome mitral valve prolapse, moyamoya disease, mucocuta two additional ways. First, by involvement of the non-conduit neous lymph node syndrome, myocardial infarction, arteries, which are detrimentally affected by the process of myocardial ischemia, myocarditis, pericarditis, peripheral atherosclerosis, and secondly, and perhaps more importantly, vascular diseases, phlebitis, polyarteritis nodosa, pulmonary by impairment of the microcirculatory control mechanisms atresia, Raynaud disease, Sneddon syndrome, Superior Vena cava syndrome, syndrome X, tachycardia, Takayasu's arteri (small vessel disease). Normally, when a body part suffers tis, hereditary hemorrhagic telangiectasia, telangiectasis, some form of trauma, the body part will, as part of the body's temporal arteritis, tetralogy of Fallot, thromboangiitis oblit healing mechanism, experience an increased blood flow. erans, thrombosis, thromboembolism, tricuspidatresia, Vari When small vessel disease and ischemia are both present, as cose veins, vascular diseases, vasculitis, vasospasm, ven in the case of many diabetics, this natural increased blood tricular fibrillation, Williams syndrome, peripheral vascular flow response is significantly reduced. This fact, together disease, varicose veins and leg ulcers, deep vein thrombosis, with the tendency of diabetics to form blood clots (thrombo Wolff-Parkinson-White syndrome. sis) in the microcirculatory system during low levels of blood 0129. Vascular diseases are often the result of decreased flow, is believed to be an important factor in ulcer pathogen perfusion in the vascular system or physical or biochemical esis. injury to the blood vessel. 0.136 Neuropathy is a general term which describes a 0130 Peripheral vascular disease (PVD) is defined as a disease process which leads to the dysfunction of the nervous disease of blood vessels often encountered as narrowing of system, and is one of the major complications of diabetes the vessels of the limbs. There are two main types of these mellitus, with no well-established therapies for either its disorders, functional disease which doesn't involve defects in symptomatic treatment or for prevention of progressive the blood vessels but rather arises from stimuli such as cold, decline in nerve function. stress, or Smoking, and organic disease which arises from 0.137 The thickening and leakage of capillaries caused by structural defects in the vasculature Such as atherosclerotic diabetes primarily affect the eyes (retinopathy) and kidneys lesions, local inflammation, or traumatic injury. This can lead (nephropathy). The thickening and leakage of capillaries to occlusion of the vessel, aberrant blood flow, and ultimately caused by diabetes are also associated with skin disorders and to tissue ischemia. disorders of the nervous system (neuropathy). US 2010/0210567 A1 Aug. 19, 2010

0.138. The eye diseases associated with diabetes are non effect as active therapeutic agents in the prophylaxis and/or proliferative diabetic retinopathy, proliferative diabetic retin treatment of heart and vascular diseases and disorders. opathy, diabetic maculopathy, glaucoma, cataracts and the like. Rare or Orphan Diseases 0.139. Other diseases, although not known to be related to 0142. Another aspect of the present invention is directed to diabetes are similar in their physiological effects on the the use of the peptide as a therapeutic agent for the prophy peripheral vascular system. Such diseases include Raynaud laxis and/or treatment of an autoimmune disease, a fibrotic syndrome, CREST syndrome, autoimmune diseases Such as disease, an inflammatory disease, a neurodegenerative dis erythematosis, rheumatoid disease, and the like. ease, an infectious disease, or a heart and vascular disease in 0140. As used herein, the term “peripheral vascular dis patients suffering from one or more of the following Rare or eases’ comprises any peripheral vascular disease including Orphan Diseases: peripheral and autonomic neuropathies. Examples of 0143 ABCD syndrome. AAE, ABSD, ACPS III, ACRP “peripheral vascular disease' include peripheral arterial dis syndrome, ACS, ACTH deficiency, isolated ACTH resis tance, ADANE, ADCA, ADCME, ADEM, ADLTE, ADULT ease, such as chronic arterial occlusion including arterioscle syndrome, AEC syndrome, AGM2, ARDS, AIDS wasting rosis, arteriosclerosis obliterans and thromboangiitis obliter syndrome, ALS, ALSG, AMME syndrome, ANOTHER syn ans (Buerger's disease), macroangiopathy, microangiopathy, drome, AOA1, AOS, APC, Autoimmune polyendocrinopa diabetes mellitus, thrombophlebitis, phlebemphraxis, thy—candidiasis—ectodermal dystrophy syndrome, APU Raynaud's disease, Raynaud's syndrome, CREST syndrome, Doma, AR-CMT, ARC syndrome, ARCA, AREDYLD health hazard due to vibration, Sudeck's syndrome, intermit syndrome, ASD, ASPED, ASPWSCR duplication, ATLD, tent claudication, cold sense in extremities, abnormal sensa ATR16, ATRUS syndrome, ATS-MR, AVED Aagenaes syn tion in extremities, sensitivity to the cold, Meniere's disease, drome, Aarskog like syndrome, Aarskog-Ose-Pande Syn Meniere's syndrome, numbness, lack of sensation, anesthe drome, Aarskog-Scott syndrome, Aase syndrome, Aase sia, resting pain, causalgia (burning pain), disturbance of Smith syndrome, Abdominal aortic aneurysm, Aberrant left peripheral circulation function, disturbance of nerve func pulmonary artery, Abetalipoproteinemia, Ablepharon mac tion, disturbance of motor function, motor paralysis, diabetic rostomia syndrome, Abruzzo-Erickson syndrome, Acalvaria, peripheral circulation disorder, lumbar spinal canal Stenosis, Acampomelic campomelic dysplasia, Acanthamoeba kerati diabetic neuropathy, shock, autoimmune disease Such as tis, Acanthocytic disorder, Acanthocytosis, Acanthosis nigri erythematosis, rheumatoid disease and rheumatoid arthritis, cans, Acatalasemia, Aceruloplasminemia, Achalasia, Achard autonomic neuropathy, diabetic autonomic neuropathy, auto Thiers syndrome, Ad Acheiropodia, Achondroplasia, Achro nomic imbalance, orthostatic hypotension, erectile dysfunc matopsia, Acitretin embryofetopathy, Ackerman syndrome, tion, female sexual dysfunction, retrograde ejaculation, cys Acoustic neurinoma, Acquired generalized lipodystrophy, topathy, neurogenic bladder, defective vaginal lubrication, Acquired hypoprothrombinemia, Acquired ichthyosis, Acquired idiopathic sideroblastic anaemia, Acquired exercise intolerance, cardiac denervation, heat intolerance, lipoatrophic diabates, Acquired prothrombin deficiency, gustatory Sweating, diabetic complication, hyperglycemia, Acrodermatitis enteropathica Zinc deficiency type, Acrodys hypoglycemia unawareness, hypoglycemia unresponsive ostosis, Acrodysplasia, Acrofacial dysostosis, Acrokerato ness; glaucoma, neovascular glaucoma, cataract, retinopathy, derma, Acrokeratoelastoidosis, Acromelanosis, Acrome diabetic retinopathy, diabetic maculopathy, occlusion of reti somelic dwarfism, Acromicric dysplasia, Acroosteolysis nal artery, obstruction of central artery of retina, occlusion of dominant type, Acrorenal defect—ectodermal dysplasia— retinal vein, macular edema, aged macular degeneration, diabetes, Acrorenal syndrome, Actinic porokeratosis dis aged disciform macular degeneration, cystoid macular seminated Superficial, Actinic porokeratosis, Acute Respira edema, palpebral edema, retinal edema, chorioretinopathy, tory Distress Syndrome, Acute basophilic leukaemia, Acute neovascular maculopathy, uveitis, iritis, retinal vasculitis, erythroblastic leukaemia, Acute febrile neutrophilic derma 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 blastic leukaemia, Acute panmyelosis with myelofibrosis, (chronic ischemic heart disease, asymptomatic ischemic Acute peripheral arterial occlusion, Acute promyelocytic leu heart disease, arteriosclerotic cardiovascular disease), myo kaemia, Acute tubulointerstitial nephritis and uveitis Syn cardial infarction, heart failure, congestive heart failure and drome, Adactylia unilateral, Adamantinoma, Adams nance painless ischemic heart disease, pulmonary edema, hyperten syndrome, Adams-Oliver syndrome. Addison's disease, Sion, pulmonary hypertension; portal hypertension, diabetic Adenine phosphoribosyltransferase deficiency, Adenosine nephropathy, decubitus, renal failure. deaminase deficiency, Adenosylcobalamin deficiency, Aden 0141. 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, US 2010/0210567 A1 Aug. 19, 2010

Adrenal adenoma, Adrenal hyperplasia, Adrenal incidenta Aspergillosis, Asphyxiating thoracic dystrophy of the new loma, Adrenal insufficiency, Ad renocortical carcinoma, born, Astley-Kendall dysplasia, Astrocytoma, Ataxia, Atelen Adrenoleukodystrophy, Adrenomyeloneuropathy, cephaly, Atelosteogenesis, Atherosclerosis, Atkin-Flaitz Syn Adrenomyodystrophy, Adult Onset Still's disease, Adult drome, Atransferrinemia, Atresia, Atrial cardiomyopathy, T-cell leukaemia/lymphoma, Adult idiopathic neutropenia, Atrial myxoma, Atrial septal defect, Atrichia, Atrioventricu Adult neuronal ceroid lipofuscinosis (Kufs disease, CLN4), lar canal complete—fallot tetralogy, Atrophia aerata, Atro Adult spinal muscularatrophy, Afibrinogenemia, African tick phoderma Vermiculata, Atypical Mole syndrome, Atypical typhus, African trypanosomiasis, Agammaglobulinemia, Werner syndrome, Aughton Sloan milad syndrome, Aughton Age-related macular degeneration, Ahn-Lerman-Sagie Syn Hufnagle syndrome, Ausems wittebol post hennekam Syn drome, Ahumada-Del Castillo syndrome, Aicardi syndrome, drome, Autism, Autoimmune haemolytic anemia, Autoim Aicardi-Goutieres syndrome, AIDS, Akaba hayasaka Syn mune lymphoproliferative syndrome, Autoimmune drome, Akesson syndrome, Alagile syndrome, Alanine-gly pancreatitits, Axenfeld-Rieger syndrome, Ayazi syndrome, oxylate aminotransferase deficiency (hyperoxaluria type 1). B-cell chronic lymphocytic leukaemia, BAFME, BBB syn Albers-Schonberg disease, Albright hereditary osteodysto drome, X-linked, BCD, BEEC, BES, BIDS syndrome, BOD phy, Alcock syndrome, Aldolase A deficiency, Aldosterone syndrome, BOFS, BOR syndrome, BOS syndrome, BPD, synthase deficiency, Aldred syndrome, Alexander disease, BRESEK syndrome, BRESHECK syndrome, BRIC, BS, Algodystrophy, Alkaptonuria, Alkylglycerone phosphate BSCL, BTHS, BTK-deficiency, Babesiosis, Bacterial toxic synthase deficiency, Allan-Herndon-Dudley Syndrome, shock syndrome, Bahemuka brown syndrome, Baird syn Allergic bronchopulmonary aspergillosis, Allgrove Syn drome, Balantidiasis, Ballard syndrome, Baller-Gerold syn drome, Alopecia, Alpers syndrome, Alpers-Huttenlocher drome, Ballooning cardiomyopathy, Balo diseases, Bamforth syndrome, Alpha-thalassemia, Alport syndrome, Alström syndrome, Bangstad syndrome, Banti Syndrome, Bannayan syndrome. Alternating hemiplegia, Alveolar echinococcosis, Riley-Ruvalcaba syndrome, Barachydactyly type A4, Barait Alves dos Santos castello syndrome, Alzheimer disease, ser burn fixen syndrome, Baraitser-Brett-Piesowicz syn Amaurosis-hypertrichosis, Ambras Syndrome, Amegacaryo drome, Barakat syndrome, Barber-Say syndrome, Bardet cytosis, Amelia, Aminoaciduria, Amoebiasis due to Entam Biedl syndrome, Bare lymphocyte syndrome, Barnicoat oeba histolytica, Ampola syndrome, Amyloid cardiopathy, baraitser syndrome, Barraquer-Simons syndrome, Barrett Amyloid nephropathy, Amyloid polyneuropathy, Amyloido eosophagus, Barth syndrome, Bartonellosis, BartSocas-Papas sis, Amylopectinosis, Amyoplasia congenita, Amyotrophic syndrome, Bartter syndrome, Basan syndrome, Bassen-Ko lateral sclerosis, Amyotrophy fat tissue anomaly, Anemia, rinzweig disease, Bassoe syndrome, Battaglia neri syndrome, Anauxetic dysplasia, Ancylostomiasis, Andermann Syn Batten disease, Baughman syndrome, BazeX syndrome, drome, Andersen disease, Aneurysmal Subarachnoid haem Bazex-Dupre-Christol syndrome, Bazopoulou kyrkanidou orrhage, Angelman syndrome, Angio-osteohypertrophic Syn syndrome, Bd syndrome, Beals syndrome, Beals-Hecht syn drome, Angiodysgenetic necrotizing myelopathy, drome, Bean syndrome, Beare Stevenson syndrome. Bech Angioedema, Angiofollicular ganglionic hyperplasia, terew syndrome, Beckwith-Wiedemann, Beemer-Ertbruggen Angiokeratoma, Angioma and vascular malformation, Angi syndrome, Behcet disease, Behr syndrome, Behrens-Bau omatosis systemic cystic Seip syndrome, Angioneurotic mann-Vogel syndrome, Bell's palsy, Bellini-Chiumello 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 (AOI), 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 US 2010/0210567 A1 Aug. 19, 2010 syndrome, Bosma henkin christiansen syndrome, Bothnia Hodgkinson syndrome, Chitty hall webb syndrome, Chitty retinal dystrophy, Boucher-Neuhauser syndrome, Bournev Hall-Baraitser syndrome, Cholera, Cholestasis, Cholesteryl ille syndrome, Boutonneuse fever, Bouwes Bavinck syn ester storage disease, Choline acetyltransferase (Ch.AT) defi drome, Bowen Syndrome, Boyadjiev-Jabs syndrome, Boylan ciency, Chondrocalcinosis, Chondrodysplasia, Chondrodys dew syndrome, Brachman-de Lange syndrome, Brachydac trophy, Chordoma, Choreoacanthocytosis, Chorioretinal tyly—arterial hypertension, Brachymesophalangy II and V. atrophy, Choristoma, Choroidal dystrophy, Choroidal sclero Brachyolmia, Braddock carey syndrome, Bradyopsia, Brain sis, Choroideremia, Christ-Siemens-Touraine syndrome, inflammatory disease, Brain injury, Brain Sclerosis, Brauer Christian syndrome, Christian-Rosenberg syndrome, Chris syndrome, Braun bayer syndrome, Braun-Tinschert, Breast tianson syndrome, Christianson-Fourie Syndrome, Christmas cancer, Brill-Zinsser disease, Brittle bone disease, Brody tree syndrome, Chromomycosis, Chronic eosinophilic pneu myopathy, Bronchial carcinoid tumour, Bronchiectasis, monia, Chronic fatigue syndrome, Chronic inflammatory Bronchiolitis obliterans organizing pneumonia, Bronchiolitis demyelinating polyneuropathy, Chronic myeloproliferative obliterans with obstructive pulmonary disease, Bronchogenic disease, Chronic neutrophilic leukaemia, Chronic pain cyst, Bronchopulmonary dysplasia, Bronspiegel-Zelnick requiring intraspinal analgesia, Chronic pneumonitis of syndrome, Brooke-Spiegler syndrome, Brown-Vialetto-van infancy, Chronic osteomyelitis, Chronic spinal muscular Laere syndrome, Bruce winship syndrome, Brucellosis, atrophy, Chudley rozdilsky syndrome, Chudley-Lowry-Hoar Bruck syndrome, Brugada syndrome, Brunner-Winter syn syndrome, Churg-Strauss syndrome, Chylomicron retention drome, Brunzell syndrome, Bruyn Scheltens syndrome, disease, Ciliary dysentery, Ciliary dyskinesia-bronchiectasis, Buckley syndrome, Budd-Chiari syndrome, Buerger's dis Cilliers-Beighton syndrome, Cirrhosis associated cardiac ease, Bull-Nixon syndrome, Bulldog syndrome, Bulimia, dysfunction, Cirrhotic cardiomyopathy, Clarkson disease, Bullous systemic lupus erythematosus, Buntinx lormans Classical Hodgkin disease, Classical homocystinuria, martin syndrome, Burkitt lymphoma, Burn-McKeown syn Claude-Bernard-Horner syndrome, ClaytonSmith-Donnai drome, Burning Mouth syndrome, Buschke-Fischer-Brauer syndrome, Cleido rhizomelic syndrome, Cleidocranial dys syndrome, Buschke-Ollendorff syndrome. Buttiens-Fryns ostosis, Cleidocranial dysplasia, Clouston syndrome, Coagu syndrome, C syndrome, CACD, CACH syndrome, CADA lation disorder, Coarctation of aorta, Coats disease, Cobb SIL, CAMAK syndrome, CAMFAK syndrome, CAMOS syndrome, Cocaine poisoning, Cockayne syndrome, Codas syndrome, CANOMAD syndrome, CAP syndrome, CAPOS syndrome, Coeliac disease, Coenzyme Q cytochrome c syndrome, CAPS (cryopyrin associated periodoc syndrome), reductase deficiency, Coffin syndrome, Coffin-Lowry syn CAR syndrome, CATCH 22, CATSHL syndrome, CAVC, drome, Coffin-Siris syndrome, Cogan syndrome, Cogan-re CCFDN, CCGE syndrome, CDA type 1, CDG syndrome, ese syndrome, Cohen hayden syndrome, Cohen lockood CDGIIc, CDP, CDPD, CEDNIK syndrome, CFC syndrome, Wyborney syndrome, Cohen syndrome, Cole carpenter Syn CHAND syndrome, CREST syndrome, CRMO, CRV, CSD, drome, Colitis, Collagen anomaly, Collins pope syndrome, CSID, CSWSS syndrome. CVID, Cacchi-Ricci disease, Cafe Collins Sakati Syndrome, Coloboma, Colon cancer, Colonic au lait spots syndrome, Caffey disease, Cahmr syndrome, atresia, Colorado tick encephalitis, Combined pituitary hor Calcinosis, Calderon gonzalez cantu syndrome, Calpainopa mone deficiencies, Complement component deficiency, Con thy, Camera lituania cohen syndrome, Campomelia Cum genital Lambert-Eaton-like syndrome, Congenital leptin ming type, Camptodactyl), Camurati engelmann disease, deficiency, Congenital lobar emphysema, Conjunctival dis Canale-Smith syndrome, Canavan disease, Candidiasis, Can ease, Conjunctival vascular anomaly, Conn syndrome, Con talamessa baldini ambrosi Syndrome, Canthus, Carbohydrate nective tissue disease, Conradi-Hinermann-Happle syn metabolism disorder, Cardiogenital syndrome, Cardiomy drome, Constrictive bronchiolitis, Cooks syndrome, Cooley opathy, Cardioskeletal myopathy, Carey fineman Ziter Syn anaemia, Cooper-Jabs syndrome, Cormier rustin munnich drome, Carnevale canun mendoza syndrome, Carnevale-Her syndrome, Corneal dystrophy, Cornelia de Lange syndrome, nandez-del Castillo syndrome, Carnevale-Krajewska Corneodermatoosseous syndrome, Corneogoniodysgenesis, Fischetto syndrome, Carney complex, Carney-Stratakis Coronaro-cardiac fistula, Coronary arterial malformations, syndrome, Carnosinase deficiency, Carnosinemia, Caroli's Coronary artery aneurysm, Coronary sinus type ASD, Cor disease, Carpal Tunnel syndrome, Carpenter syndrome, Car tada koussef matsumoto syndrome, Costeff optic atrophy penter-Waziri syndrome, Carrington's disease, Carrion dis syndrome, CoSteff syndrome, Costello syndrome, Cote kat ease, Carvajal syndrome, Casamassima-Morton-Nance Syn Santoni syndrome, Cousin-Walbraum-Cegarra syndrome, drome, Cassia Stocco dos Santos syndrome, Castleman Cowchock syndrome, Cowchock-Wapner-Kurtz syndrome, disease, Castro gago pombo novo syndrome, Catalase defi Cowden syndrome, Coxoauricular syndrome, Cramer-Nie ciency, Cataract, Catel-Manzke syndrome, Cayler syndrome, derdellmann syndrome, Crandall syndrome, Crane heise Syn Celiac disease, Celosomia, Cenani lenZ Syndactylism, Cen drome, Cranial malformation, Craniopharyngioma, Cranio tral neurocytoma, Cephalopolysyndactyl), Ceramidase defi rachischisis, Craniostenosis, Craniosynostosis, ciency, Cerebellar hypoplasia, Cerebral arteriovenous shunt, Craniotelencephalic dysplasia, Craniotubular syndrome, Cerebral hemorrhage with amyloidosis, Cerebroretinal vas Creatine deficiency, Creeping disease, Creutzfeldt-Jakob dis culopathy, Cfc syndrome, Chagas disease, Chanarin disease, ease, Cri du chat syndrome, Crigler-Najjar syndrome, Chandler syndrome, Chang-Davidson-Carlson syndrome, Crimean-Congo haemorragic fever (CCHF), Crisponi syn Chaotic atrial tachycardia, Char douglas dungan syndrome, drome, Criss-cross heart, Criswick-Schepens syndrome, Char syndrome, Charge syndrome, Charlevoix disease, Char Crohn disease, Crome syndrome, Cronkhite canada Syn lie m syndrome, Chediak-Higashi like syndrome, Cheilitis drome, Cross syndrome, Crouzon disease, Crow-Fukase Syn glandularis, Chemke oliver mallek syndrome, Chemodec drome, Cryoglobulinaemia mixed, Cryptococcosis, Crypto toma, Chemy-red-spot myoclonus syndrome, Cherubism, genic organizing pneumonia, Cryptophthalmia, Chiari Frommel syndrome, Chitayat hajchahine syndrome, Cryptosporidiosis, Culler-Jones syndrome, Currarino triad, Chitayat moore del bigio syndrome, Chitayat-Meunier Curry-Hall syndrome, Curry-Jones syndrome, Cushing dis US 2010/0210567 A1 Aug. 19, 2010 ease, Cutaneomeningospinal angiomatosis, Cutaneous lupus Dubin-Johnson syndrome, Dubowitz syndrome, Duhring erythematosus, Cutaneous mastocytoma, Cutaneous masto brocq disease, Duker-Weiss-Siber syndrome, Dunnigan Syn cytosis, Cutaneous photosensitivity colitis, Cutaneous vascu drome, Dupont sellier chochillon syndrome, Dyggve-Mel litis, Cutaneuous myiasis, Cutis laxa, Cutler bass rom she chior-Clausen disease, Dykes-Markes-Harper syndrome, syndrome, Cyclosporosis, CyStathioninuria, Cystic fibrosis, Dyschondrosteosis, Dyschromatosis universalis, Dysferlin Cystic hamartoma of lung and kidney, Cystic lymphangioma, opathy, Dysfibrinogenemia, Dyskeratosis, Dysmorphic Syn Cystic renal disease, Cystinosis, Cystinuria, Cytochrome c drome with connective tissue involvement, Dysosteosclero oxydase deficiency, Cytomegalovirus (CMV) disease in sis, Dysostosis, Dysphagia lusoria, Dysplasia, patients with impaired cell mediated immunity deemed at Dysprothrombinemia, Dyssegmental dysplasia glaucoma, risk, Cytopenia, Czeizel brooser syndrome, Czeizel losonci Dysspondyloenchondromatosis, Dystoni-like syndrome with syndrome, Dercole syndrome, D-2-hydroxyglutaricaciduria, paroxysmal disease, Dystonia, EBD, EBJ, EBS, ECP syn D-glycerate dehydrogenase deficiency (hyperoxaluria type drome, EDS III, EEC syndrome, EEM syndrome, EGE, ENT, 2), D-glycerate kinase deficiency, D-glycericacidemia, ERA, ESS1, Eagle-Barret syndrome, Eales disease, Ebola DCMA syndrome, DCMD, DEND syndrome, DI-CMT, virus disease, Echinocytic disorder, Ectodermal dysplasia, DIDMOAD syndrome (Diabetes Insipidus-Diabetes Melli Ectromelia, Ectropion, Eczema-thrombocytopenia-immuno tus-Optic Atrophy-Deafness), DIS, DK phocomelia syn deficiency syndrome, Edinburgh malformation syndrome, drome, DKC, DOOR syndrome, DORV, DTDP1, DYT6, Da Edward syndrome, Edwards-Patton-Dilly syndrome, Ehlers silva syndrome, Dacryocystitis osteopoikilosis, Daentl Danlos Syndrome, Ehrlichiosis, Eiken syndrome, Eisen Townsend-Siegel syndrome, Dahlberg-Borer-Newcomer menger syndrome, Elastosis perforans serpiginosa, Elejalde syndrome, Daish hardman lamont syndrome, Dancing Eye syndrome, Elliott ludman teebi syndrome, Elliptocytosis, syndrome, Dandy walker malformation, Daneman davy Ellis Van Creveld syndrome, Ellis yale winter syndrome, mancer syndrome, Danon disease, Darier disease, Darier Elsching syndrome, Emanuel syndrome, Emery-Dreifuss Gottron disease, Davenport donlan syndrome, David Syn muscular dystrophy, Emery-Nelson syndrome, Empty Sella drome, Davies disease, Davis lafer syndrome, De Barsy syn syndrome, Encephalitis, Encephalomyelitis, Encephalopa drome, De Hauwere-Leroy-Adriaenssens syndrome, De thy, Enchondromatosis, Endometriosis, Endotheliitis, Eng Santis-Cacchione syndrome, De Smet-Fabry-Fryns syn strom Syndrome, Engel congenital myasthenia, Engelhard drome, De Vaal disease, De la Chapelle dysplasia, Demorsier yatziv Syndrome, Enolase deficiency, Entericanendocrinosis, syndrome, Deafness-Small bowel diverticulosis-neuropathy, Enteropathy, Enterovirus antenatal infection, Entropion, Dealbarratt dillon syndrome, Degos disease, Deerine-Sottas Envenomization, Eosinophilic endocarditis, Eosinophilic syndrome, Dekaban-Arima syndrome, Delayed graft func pneumonia, Ependymoma, Epidermolysis bullosa, Epilepsy, tion after organ transplantation, Delleman-Oorthuys syn Epiphyseal dysplasia, Episodic ataxia, Epispadias, Epithelial drome, Dementia associated with a metabolic disease, ovarian cancer, Epithelioma, Epstein-Barr virus infection, Dementia associated with a neurodegenerative disease, Erdheim disease, Erdheim-Chester disease, Eronen-Somer Dementia associated with an infectious disease, Dementia Gustafsson syndrome, Erythema, Erythermalgia, Erythro associated with hepatic and renal failure, Demodicidosis, blastopenia, Erythrocytosis, Erythroderma, Erythrokerato Dendritic cell sarcoma, Dendritic cell tumor, Dengue, Dennis derma, Erythromelalgia, Escher hirt syndrome, Escobar cohen syndrome, Dennis fairhurst moore syndrome, Dense syndrome, Esophageal adenocarcinoma, Esophageal atresia, (delta) granule disease, Dent disease, Dentin dysplasia, Essential cryoglobulinaemia, Essential iris atrophy, Essential Denys-Drash syndrome, Der Kaloustian-Jarudi-Khoury syn osteolysis, Esthesioneuroblastoma, Estrogen receptor defi drome, Der kaloustian mcintosh silver syndrome, Dercum’s ciency, Estrogen resistance syndrome, Evans syndrome, disease, Dermatofibrosarcoma protuberans, Dermatologic Ewing sarcoma, Exner syndrome, Exostoses, EXSudative ret allergic disease, Dermatostomatitis Stevens Johnson type, inopathy, Extracutaneous mastocytoma, Extrinsic allergic Desbuquois Syndrome, Desminopathy, Desmoid disease, alveolitis, Eye disease, F syndrome, FAP, FAS deficiency, Desmosterolosis, Devic's disease, Devriendt legius fryns FCS syndrome, FCU, FENIB, FEOM, FFDD type I, FG syndrome, DeVriendt vandenberghe fryns Syndrome, syndrome, FLOTCH syndrome, FOP, FOSMN syndrome, DiGeorge syndrome, Diabetes, Dialysis-related arthropathy, FPS/AML syndrome, FRAXA syndrome, FRAXE syn Diaphanospondylodysostosis, Diaphragmatic agenesia, Dia drome, FRAXF syndrome, FSH resistance, Fabry disease, phragmatic spinal muscular atrophy, Diffuse alveolar haem Factor VII deficiency, Factor VIII deficiency, Factor X defi orrhage. Diffuse large B cell lymphoma, Diffuseleiomyoma ciency, Factor XI deficiency, Factor XII deficiency, Factor tosis—Alport syndrome X-linked. Diffuse neonatal XIII deficiency, Factors II, VII, IX and X, combined defi haemangiomatosis, Dihydropyrimidinuria, Dilated cardi ciency, Fahr syndrome, Fallot complex, Familial LCAT defi omyopathy with ataxia, DincSoy-Salih-Patel syndrome, ciency, Fanconi anaemia, Fanconi ichthyosis dysmorphism, Dinno shearer weisskopf syndrome, Diomedibernardi pla Fanconi syndrome, Fanconi-Bickel disease, Fara-Chlu cidi syndrome, Dionisi-Vici-Sabetta-Gambarara syndrome, packova syndrome, Farber lipogranulomatosis, Farmer's Diphtheria, Diprosopia, Discoid lupus erythematosus, Dis lung disease, Fatal infantile COX deficiency, Faulk-Epstein crete fibromuscular Subaortic Stenosis, Distichiasis—con Jones syndrome, Favism, Fazio-Londe disease, Fechtner Syn genital heart defects peripheral vascular anomalies, Disto drome, Feigenbaum-Bergeron-Richardson syndrome, Fein matosis, Dobrow syndrome, Donath-Landsteiner syndrome, gold syndrome, Felty syndrome, Fenton wilkinson toselano Donnai-Barrow syndrome, Donohue syndrome, Doose Syn syndrome, Ferlini-Ragno-Calzolari syndrome, Fernhoff drome, Dorfman-chanarin disease, Dowling-Degos disease, BlackSton-Oakley Syndrome, Fetal cytomegalovirus Syn Dowling-Degos-Kitamura disease, Down syndrome, Doyne drome, Fetal edema, Fetal left ventricular aneurysm, Fibrino honeycomb retinal dystrophy (DHRD), Drachtman weinblatt gen disorder, Fibrochondrogenesis, Fibrodysplasia ossificans sitarZ Syndrome, Drash syndrome, Dravet syndrome, Drum progressiva, Fibromatosis, Fibromuscular dysplasia of arter mond syndrome, Du Pan syndrome, Duane syndrome, ies, Fibromyalgia, Fibronectin glomerulopathy, Fibrosar US 2010/0210567 A1 Aug. 19, 2010

coma, Fibrosing mediastinitis, Fibrosis of extraocular syndrome, Goodpasture syndrome, Goossens-DeVriendt Syn muscles, Fiessinger-Leroy-Reiter's syndrome, Figuera syn drome, Gordon syndrom, Gorham syndrome, Gorham-Stout drome, Filamin anomaly, Filariasis, Filippi Syndrome, Fine disease, Gorlin syndrome, Gorlin-Chaudhry-Moss syn Lubinsky syndrome, Finlay-Markes syndrome, Finucane drome, Graft rejection after lung transplantation, Graft versus kurtz scott syndrome, Fitz Hugh Curtis syndrome, Fitzsim host disease, Graham boyle troxell syndrome, Graham-Cox mons-Guilbert syndrome, Fitzsimmons-McLachlan-Gilbert syndrome, Grand-Kaine-Fulling syndrome, Grange occlu syndrome, Fitzsimmons-Walson-Mellor syndrome, Fixed sive arterial syndrome, Grant syndrome, Granulocytic sar Subaortic Stenosis, Flegel disease, Floating-Harbor Syn coma, Granulomatous allergic angiitis, Granulomatous drome, Florid cemento-Osseous dysplasia, Flynn aird syn inflammatory arthritis, dermatitis, and uveitis, Granuloma drome, Foix chavany marie syndrome, Foix-Alajouanine tous mastitis, Graves' disease, Gray platelet syndrome, syndrome, Follicular atrophoderma-basal cell carcinoma, Greenberg dysplasia, Greig syndrome, Greither's disease, Follicular dendritic cell sarcoma, Follicular dyskeratoma, Griscelli disease, Grix blankenshippeterson syndrome, Groll Follicular ichthyosis, Follicular lymphoma, Fontaine-Farri hirschowitz syndrome, Gronblad-Strandberg-Touraine syn aux-Blanckaert syndrome, Forbes disease, Formey-Robin drome, Grosse syndrome, Grover's disease, Growth hormone son-Pascoe syndrome, Forunculoid myiasis, Fountain Syn deficiency, Grubben de cock borghgraef syndrome, Gräs drome, Fowler-Christmas-Chapple syndrome, Fox Fordyce beck-Imerslund disease, Guam disease, Guanidinoacetate disease, Fra-X syndrome, Fragile X syndrome, Fragoso cid methyltransferase deficiency, Guibaud-Vainsel syndrome, garcia hernandez syndrome, Franceschetti-Klein syndrome, Guillain-Barré syndrome, Guizar-Vasquez-Luengas syn Francois dyscephalic syndrome, Francois Syndrome, Franek drome, GuizarVazquez-Sanchez-Manzano syndrome, Gunal bockerkahlen syndrome, Frank-Ter Haar syndrome, Franklin seber basaran syndrome, Gurrieri-Sammito-Bellussi syn disease, Fraser like syndrome, Fraser syndrome, Frasier Syn drome, Gusher syndrome, Gynandroblastoma, Günther dis drome, Freeman-Sheldon syndrome, Freiberg's disease, ease, HAD deficiency, HAE, HAIRAN syndrome, HANAC Freire maia pinheiro opitz syndrome, Frey's syndrome, Frias syndrome, HARD syndrome (Hydrocephalus-agyria-retinal syndrome, Fried syndrome, Fried-Goldberg-Mundel syn dysplasia), HCDD, HCL, HDL metabolism disorder, HEM, drome, Friedman goodman syndrome, Friedreich ataxia, HEPHERNS syndrome, HHE syndrome, HHT, HHV-8, HID Froelich's syndrome. Froster-Huch syndrome, Froster-Iske syndrome, HIGM1, HIT, HMSN 5, HMSNP, HNPCC, nius-Waterson syndrome, Fructosuria, Frydman-Cohen-Kar HNSCC, HPA-1 deficiency, HPE, HSAN 1, HSD deficiency, mon syndrome, Fryns macrocephaly, Fryns-Aftimos Syn HSV encephalitis, HSV keratitis, HUS, HVR, Haas-Robin drome, Fryns-Hofkens-Fabry syndrome, Fuhrmann-Rieger son syndrome, Haddad syndrome, Haematologic cancers, de Sousa syndrome, Fukuda miyanomae nakata syndrome, Haemochromatosis, Haemoglobin disorders, Haemolysis, Fukuhara syndrome, Fuqua-Berkovitz syndrome, Furlong Haemolytic anaemia, Haemolytic uremic syndrome, Haem syndrome, Furukawatakagi nakao Syndrome, G syndrome, orrhagic fever, Haemorrhagiparous thrombocytic dystrophy, G6PD deficiency, GABA metabolism disease, GAMT defi Hageman factor deficiency, Hagemoser weinstein bresnick ciency, GAPO syndrome, GIST, GM1 gangliosidosis, syndrome, Hailey-Hailey disease, Haim-Munk syndrome, GOSHS, GRACILE syndrome, GRF Tumour, GSD, GTN, Hairy cell leukaemia, Hajdu-Cheney syndrome, Hal-Berg GVH, Gaisbock syndrome, Galactokinase deficiency, Galac Rudolph syndrome, Halal syndrome, Halal-Setton-Wang tosemia, Galactosialidosis, Galloway syndrome, Galloway syndrome, Hallermam streiff like syndrome, Hallermann Mowat Syndrome, Gamborgnielsen syndrome, Game-Fried Streiff-Francois syndrome, Hallervorden-Spatz disease, man-Paradice syndrome, Gamstorp episodic adynamy, Hamanishi ueba tsuji Syndrome, Hamano tsukamoto Syn Ganglioglioma, Garcia torres guarner syndrome, Garcia-Lu drome, Hamman-Rich syndrome, Hanhart syndrome, Hand rie Syndrome, Gardner silengo wachtel syndrome, Gardner Foot Mouth syndrome, Hand-Shuller-Christian disease, Morrison-Abbott syndrome, Garret tripp syndrome, Gastric Hanot syndrome, Hantavirus pulmonary syndrome, Hapnes cancer, Gastroschisis, Gaucher disease, Gaucher-like disease, boman skeie Syndrome, Happy puppet syndrome, Harboyan Geen Sandford davison syndrome, Gelineau disease, Gemig syndrome, Hardcastle syndrome, Harding ataxia, Harrod nani syndrome, Gemss syndrome, Genes syndrome, Geno syndrome, Harrod-Keele syndrome, Hartnup disorder, Harts chondromatosis, Gerbode defect, Gerhardt syndrome, Ger field bixler demyer syndrome, Hashimoto struma, Hash man syndrome, Gershonibaruch-Leibo syndrome, imoto-Pritzker syndrome, Haspeslagh-Fryns-Muelenaere Gerstmann-Straussler-Scheinker syndrome, Ghosal Syn syndrome, Hawkinsinuria, Hay wells syndrome, Heart block drome, Gianotti Crosti syndrome, Giant cell arteritis, Giant progressive, Heart-hand syndrome, Heavy chain deposition platelet syndrome, Gilbert syndrome, Gilles de la Tourette disease, Hec syndrome, Hecht Scott syndrome, Heckenlively syndrome, Gillespie syndrome, Gitelman syndrome, Glan syndrome, Heide syndrome, Heimler syndrome, Heiner Syn Zmann thrombasthenia, Glass bone disease, Glass-Chapman drome (cow’s milk hypersensitivity), Helmerhorst heaton Hockley syndrome, Glaucoma, Glioblastoma, Glomerular crossen syndrome, Hemangioma-thrombocytopenia Syn disease, Glomerulonephritis, Glomerulopathy with fibronec drome, Hemangiopericytoma, Hematopoietic hypoplasia, tin deposits (GFND), Gloomy syndrome, Glucagonoma, Hemeralopia, Hemi 3 syndrome, Hemiconvulsion-Hemiple Glucocorticoid resistance, Glycogen storage disease, Gms gia-Epilepsy syndrome, Hemifacial hyperplasia Strabismus, syndrome, Goiter-deafness syndrome, Golabi-Rosen Syn Hemihypertrophy intestinal web cornealopacity, Hemimelia, drome, Goldberg syndrome, Goldberg-Maxwell syndrome, Hemitruncus, Hemochromatosis, Hemoglobin C disease, Goldberg-Shprintzen megacolon syndrome, Goldblatt vil Hemoglobin E disease, Hemoglobin H disease, Hemolytic joen Syndrome, Goldblatt wallis syndrome, Goldenhar Syn anaemia, Hemophilia, Hemorrhagiparous thrombocytic dys drome, Goldmann-Favre syndrome, Goldstein huff syn trophy, Hennekam koss de geest syndrome, Hennekam Syn drome, Goldston syndrome, Gollop syndrome, Gollop drome, Hennekam-Beemer syndrome, Henoch-Schoenlein wolfgang complex, Goltz syndrome, Goltz-Gorlin syndrome, purpura, Hepatic cystic hamartoma, Hepatic fibrosis, Hepatic Gombo syndrome, Gonzales del angel syndrome, Goodman cancer, Hepatic venoocclusive disease, Hepatitis B re-infec US 2010/0210567 A1 Aug. 19, 2010 tion following liver transplantation, Hepatitis, Hepatoblas Idiopathic hypereosinophilic syndrome, Idiopathic infantile toma, Hepatocellular adenoma, Hepatocellular carcinoma, arterial calcification, Idiopathic infection caused by BCG or Hepatoerythropoeitic porphyria, Hepatoportal sclerosis, atypical mycobacteria, Idiopathic interstitial pneumonia, Hereditary coproporphyria, Hereditary endotheliopathy-ret Idiopathic juvenile osteoporosis, Idiopathic myelofibrosis, inopathy-nephropathy-stroke, Hereditary lymphoedema type Idiopathic obliterative arteriopathy, Idiopathic orthostatic I, Hereditary motor and sensory neuropathy, Hereditary vas hypotension, Idiopathic pulmonary fibrosis, Idiopathic cular retinopathie-Raynaud phenomenon-migraine, Herman thrombocytopenic purpura, leshima-Koeda-Inagaki Syn sky-Pudlak syndrome, Hernandez fragoso syndrome, Her drome, Illum syndrome, Ilyina amoashy grygory syndrome, nandez-Aguirre Negrete syndrome, Herpes virus infection, Imaizumi kuroki syndrome, Immune thrombocytopaenia, Herrmann opitz arthrogryposis syndrome, Hers disease, Immunodeficiency, Immunoproliferative Small intestinal dis Hersh-Podruch-Weisskopf syndrome, Herva disease, Hetero ease, Infant respiratory distress syndrome, Insulin-resistance taxia, Heterozygous OSMED, Hillig syndrome, Hinman syn syndrome, Insulinoma, Interdigitating dendritic cell sarcoma, drome, Hinson-Pepys disease, Hipo syndrome, Hirayama Intermediate DEND syndrome, Intermediate spinal muscular disease, Hirschsprung disease, Hirsutism, His bundle tachy atrophy, Internal carotid agenesis, Interstitial cystitis, Inter cardia, Histidine metabolism disorder, Histidinuria renal Stitial granulomatous dermatitis with arthritis, Interstitial tubular defect, Histiocytic and dendritic cell tumour. Histio pneumonia, Interventricular septum aneurysm, Intestinal cytic sarcoma, Histiocytoid cardiomyopathy. Histiocytosis atresia multiple, Intestinal epithelial dysplasia, Intestinal X, Histoplasmosis, Hittner hirschkreh syndrome, Hmc syn hypomagnesemia with secondary hypocalcemia, Intestinal drome, Hodgkin lymphoma, Hoepffner dreyer reimers Syn lipodystrophy, Intestinal lipophagic granulomatosis, Intesti drome, Hoffman's syndrome, Holmes benacerraf syndrome, nal lymphangiectasia, Intestinal pseudoobstruction, Intrac Holmes collins syndrome, Holmes-Gang syndrome, Holoac erebral haemorrhage, Intracranial aneurysms, Intracranial ardius amorphus, Holoprosencephaly, Holt-Oram syndrome, arterioVeinous malformation, Inverse Marcus-Gunn phenom Holzgreve Wagner rehder syndrome, Homocarnosinosis, enon, Iridocorneal endothelial syndrome, Iridogoniodysgen Homocystinuria, Homogentisic acid oxydase deficiency, esis, Irons-Bhan syndrome, Irritable bowel syndrome, Isaac's Hoon hall syndrome, Horner syndrome, Horton disease, syndrome, Isaacs mertens syndrome, Ischaemic brain injury, Houlston ironton temple syndrome, House allergicalveolitis, Ischemia/perfusion injury associated with Solid organ trans Howard young syndrome, Howell-Evans syndrome, Hoyer plantation procedure, Ischio-vertebral dysplasia, Iso-Kikuchi aal-Hreidarsson syndrome, Humeroradial Synostosis, syndrome, Isosporiasis, Isotretinoin syndrome, Isotretinoin Humeroradioulnar synostosis, Humerospinal dysostosis, like syndrome, Isovaleric acidemia, Itin syndrome, Ito Hunter carpenter mc donald Syndrome, Hunter jurenka hypomelanosis, Ivemark syndrome, JAE, JWS, Jackson-Barr thompson syndrome, Hunter syndrome, Hunter-Rudd-Hoff syndrome, Jackson-Weiss Syndrome, Jacobs syndrome, mann syndrome, Hunter-Thompson-Reed syndrome, Hun Jacobsen syndrome, Jaffe campanacci syndrome, Jaffe-Lich tington disease, HurieZ Syndrome, Hurler syndrome, Hurler tenstein disease, Jagell holmgrenhofer syndrome, Jalili Syn Scheie syndrome, Hutchinson-Gilford syndrome, Hutteroth drome, Jancar syndrome, Japanese encephalitis, Jarcho spranger syndrome, Hyaline membrane disease, Hyalu Levin Syndrome, Jaw-Winking syndrome, Jensen syndrome, ronidase deficiency, Hydatidosis, Hyde-Forster-Mccarthy Jequier-Kozlowski syndrome, Jervell and Lange-Nielsen 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 carlson 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 US 2010/0210567 A1 Aug. 19, 2010 20 syndrome, Kenny-Caffey syndrome, Kenya tick-bite fever, gryposis with anterior horn cell disease (LAAHD), Lethal Keratinisation disorder associated with genetic eye disease, chondrodysplasia moerman type, Lethal congenital contrac Keratitis, Keratoacanthoma, Keratoconus, Keratoderma, ture syndrome, Lethal osteosclerotic bone dysplasia, Let Keratosis, Kerion celsi, Kersey Syndrome, Ketoacidosis, terer-Siwe disease, Leucinosis, Leukaemia, Leukocyte adhe Ketoaciduria, Ketolysis disorder, Keutel syndrome, KGB sion deficiency (LAD), Leukodystrophy, syndrome, Khalifa-Graham Syndrome, Kienbock disease, Leukoencephalopathy, Leukonychia totalis, Leukotriene C4 Kikuchi disease, Kikuchi-Fujimoto disease, Kimura disease, (LTC4) synthase deficiency, Levic Stefanovic nikolic Syn King-Denborough syndrome, Kinsbourne syndrome, drome, Levine-Critchley syndrome, Levocardia, Levy-Hol Klatskin tumour, Klein-Waardenburg syndrome, Kleine lister syndrome, Levy-Yeboa syndrome, Lewis-Pashayan Levin syndrome, Kleiner holmes syndrome, Klinefelter syn syndrome, Lewis-Sumner syndrome, Lewy body dementia, drome, Klippel-Feil malformation, Klippel-Trenaunay Syn Leydig cell hypoplasia, Lhermitte-Duclos disease, Li-Frau drome, Kluver-Bucy syndrome, Kniest dysplasia, Knobloch meni syndrome, Lichen, Lichstenstein syndrome, Liddle Syn layer syndrome, Kocher-Debre-Semelaigne syndrome, drome, Lindsay-Burn syndrome, Linear hamartoma Syn Kohler's disease, Kohlschutter-Tonz syndrome, Kok disease, drome, Linitis plastica, Lip-pit syndrome, Lipid storage Komar syndrome, Konigsmark knox hussels syndrome, disease, Lipodystrophy, Lipodystrophy-HIV related, Kopysc barczyk krol syndrome, Kosenow syndrome, Kost Lipoedema, Lipoid proteinosis, Lipomatosis, Lipoprotein mann syndrome, Kosztolanyi syndrome, Koussef nichols metabolism disease, Liposarcoma, Lisker-Garcia-Ramos syndrome, Kousseff syndrome, Kowarski syndrome, syndrome, Lissencephaly, Listeriosis, Little syndrome, Kozlowski brown hardwick syndrome, Kozlowski massen Lobaratrophy of brain, Lobstein disease, Lobster-claw defor syndrome, Kozlowski ouvrier syndrome, Kozlowski tsuruta mity, Localized Castleman disease, Localized scleroderma, syndrome, Kozlowski-Krajewska syndrome, Krabbe disease, Locked-in syndrome, Loeffler's endocarditis, Loeys-Dietz Krasnow-Qazi syndrome, Krauss herman holmes syndrome, syndrome, Loffredo cennamo cecio syndrome, Logic Syn Kudo tamura fuse syndrome, Kugelberg-Welander disease, drome, Loiasis, Long QT syndrome, Longman-Tolmie Syn Kumar-Levick syndrome, Kunzeriehm Syndrome, Kurczyn drome, Loose anagen syndrome, Lopes gorlin syndrome, ski-Casperson syndrome, Kuskokwim disease, Kuzniecky Lopes marques de faria syndrome, Lopez-Hernandez Syn syndrome, Kynureninase deficiency, Kyphomelic dysplasia, drome, Lou-Gehrig disease, Louis-Bar syndrome, Lowe Kyphosis brachyphalangy optic atrophy, Kussmaul-Maier kohn cohen syndrome, Lowe oculocerebrorenal syndrome, disease, L1 syndrome, L-2-hydroxyglutaricaciduria, LADD Lowe syndrome, Lower mesodermal defects, Lown-Ganong syndrome, LBSL, LBWC syndrome, LCAD, LCAT defi Levine syndrome, Lowry syndrome, Lowry-MacLean syn ciency, LCCS, LCDD, LCH, LCHAD deficiency, LDD, drome, Lowry-Yong syndrome, Lubani-Al Saleh-Teebi syn LEOPARD syndrome, LGMD, LHCDD, LIG4 syndrome, drome, Lubinsky syndrome, Lubs-Arena Syndrome, Lucey LMS, LORD, LPI, Laband syndrome, Lachiewicz sibley syn driscoll Syndrome, Lucky gelehrter syndrome, Lujan-Fryns drome, Lactate dehydrogenase deficiency, Lactic acidosis, syndrome, Lunatomalacia, Lundberg syndrome, Lung agen Lactotrophadenoma, Ladda Zonanaramer syndrome, Lafora esis heart defect thumb anomalies, Lung cancer Small cell, disease, Laing distal myopathy, Lambdoid synostosis, Lam Lung fibrosis, Lupus erythematosus, Luriekletsky syndrome, bert syndrome, Lambert-Eaton myasthenic syndrome, Luteinizing hormone releasing hormone deficiency with 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, MOBA 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 US 2010/0210567 A1 Aug. 19, 2010

ease, Maffucci syndrome, Majeed syndrome, Majewxki drome, Mikati naijar Sahli syndrome, Mikulicz disease, Mild orturk syndrome, Major airway collapse, Meleda disease, campomelic dysplasia, Miller syndrome, Miller-Dieker syn Malakoplakia, Malakoplasia, Malaria, Malignant fibrous his drome, Miller-Fisher syndrome (MFS), Mills syndrome, Mil tiocytoma, Malignant germ cell tumor, Malignant hyperpyr roy disease, Minimal change nephrotic syndrome (MCNS), exia, Malignant hyperthermia, Malignant mesenchymal Minkowski-Chauffard disease, Mirhosseini-Holmes-Walton tumor, Malignant paroxysmal ventricular tachycardia, Mal syndrome, Mitral valve prolapse disease, Miura syndrome, lory Weiss syndrome, Malouf syndrome, Maltase-glucoamy Mixed connective tissue disease, Mixed phenotype acute leu lase deficiency, Maniac-depressive disorders, Manouvrier kaemia, Mixed Sclerosing bone dystrophy, Miyoshi myopa syndrome, Mansonellosis, Mantle cell lymphoma, Maple thy, MIs syndrome, Moderate and severe traumatic brain syrup urine disease, Marashi gorlin syndrome, Marble brain injury, Moebius syndrome, Moerman Vandenberghe fryns disease, Marburg disease, Marchiafava-Micheli disease, syndrome, Moersch-Woltman syndrome, Moeschler clarren Marcus-Gunn syndrome, Marden walker like syndrome, syndrome, Mohr syndrome, Mohr-Tranebaerg syndrome, Marfan syndrome, Margarita island ectodermal dysplasia, Mollica pavone antener syndrome, Moloney syndrome, Marin-Amat syndrome, Marinesco-Sjogren syndrome, Momo syndrome, Monilethrix, Mononen-Karnes-Senac syn Marion mayers syndrome, Markel-Vikkula-Mulliken syn drome, Monostotic fibrous dysplasia, Montefiore syndrome, drome, Marles greenberg persaud syndrome, Maroteaux Moore-Federman syndrome, Morava-Mehes syndrome, cohen solalbonaventure syndrome, Maroteaux le merrer ben Morgagni-Stewart-Morel syndrome, Morillo cucci passarge Sahel Syndrome, Maroteaux stanescu cousin Syndrome, syndrome, Morning glory syndrome, Morquio disease, Mor Maroteaux-Lamy syndrome, Maroteaux-Malamut Syn ris syndrome, Morse rawnsley Sargent syndrome, Morvan drome, Marsden nyhan Sakati Syndrome, Marshall syndrome, syndrome, Moschcowitz disease, Mounier-Kuhn syndrome, Marshall-Smith syndrome, Martinez monasterio pinheiro Mousa-Al Din-Al Nassar syndrome, Movement disease, syndrome, Martinez-Frias syndrome, Martsolf syndrome, Mowat-Wilson syndrome, Moya-moya disease, Moynahan Massa casaer ceulemans syndrome, Mast cell leukaemia, syndrome, Mpo deficiency, Msbd syndrome, Mseleni joint Mast cell sarcoma, Mastocytosis, Mastroiacovo de rosa Satta disease (MJD), Mucha Habermann Disease. Muckle-Wells syndrome, Mathieu de broca bony Syndrome, Matsoukas syndrome, Mucoepithelial dysplasia, Mucolipidosis, Muco liarikos giannika syndrome, Matthew-Wood syndrome, polysaccharidosis, Mucormycosis, Mucosal pemphigoid, Mature B-cell tumour, Mature T-cell and NK-cell tumour, Mucosulfatidosis, Muenke syndrome, Muir-Torre syndrome, May-Hegglin thrombocytopenia, Mayer-Rokitansky-Küster Mullerian aplasia, Multicentric Castleman disease (MCD), Hauser syndrome, Mazabraud syndrome, McArdle disease, Multicentric giant lymph node hyperplasia, Multicentric McCabe's disease, McCune-Albright syndrome, McDon osteolysis, Multifocal acquired demyelinating sensory and ough syndrome, McDowall syndrome, McGrath syndrome, motor neuropathy, Multifocal pattern dystrophy simulating McKusick-Kaufman syndrome, McLeod syndrome, fundus flavimaculatus, Multiglandular hyperplasia, Multi McPherson-Hall syndrome, Mcalister crane syndrome, minicore disease (MmD), Multinodular goiter cystic kidney Mccallum macadam johnston syndrome, Mcgillivray Syn polydactyl), Multiple carboxylase deficiency, Multiple con drome, Mclain-Dekaban syndrome, Mcpherson clemens Syn tracture syndrome, Multiple cutaneous and uterine leiomyo drome, Meacham winn culler syndrome, Meadows syn mas, Multiple endocrine neoplasia, Multiple epiphyseal dys 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, Myelinosis 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, US 2010/0210567 A1 Aug. 19, 2010 22

Nakajo nishimura syndrome, Nakajo syndrome, Nakamura heim's dystonia, Opsismodysplasia, OpSoclonus-myoclonus osame syndrome, Nance-Horan syndrome, Narcolepsy with syndrome, Optic atrophy, Optic nerve hypoplasia, Optic neu out cataplexy, Narcolepsy-Cataplexy, Nasodigitoacoustic ropathy, Optic pathway glioma, Orbital leiomyoma, syndrome, Nasopharyngeal cancer, Nasu-Hakola disease, Ormond's disease, Ornithine aminotransferase deficiency, Nathalie syndrome, Navajo brainstem syndrome, Naxos dis Orofaciodigital syndrome, Oromandibular dystonia, Oroti ease, Necrotising hypophysitis, Necrotizing myelitis, Nema caciduria, Oroya fever, Osebold-Remondini syndrome, line myopathy, Neonatal Onset Multisystem Inflammatory Osgood-Schlatter disease, Osler-Vaquez disease, Osteoarthr Disease, Neonatal death immune deficiency, Neonatal hemo opathy, Osteoblastoma, Osteochondritis, Osteochondromas, chromatosis, Neonatal neutropenia, Neonatal respiratory dis Osteochondrosis, Osteocraniostenosis, Osteodysplasia, tress syndrome, Nephroblastoma, Nephrogenic fibrosing der Osteoectasia, Osteogenic sarcoma, Osteolysis, Osteome mopathy, Nephrogenic systemic fibrosis, Nephrolithiasis, Sopyknosis, Osteonecrosis, Osteopaenia, Osteopathia striata Nephronophthisis-hepatic fibrosis, Nephropathy, Nephrosis, cranial sclerosis, Osteopetrosis, Osteopoikilosis, Osteoporo Nephrotic syndrome with diffuse mesangial sclerosis, Neph sis, Osteosarcoma, Osteosclerosis, Ostravik lindemann rotic syndrome, Nervous system tumour, Netherton disease, solberg syndrome, Otosclerosis, Ouvrier billson syndrome, Neu-Laxova Syndrome, Neuhauser daly magnelli syndrome, Ovarian Sertoli-Leydig cell tumor, Ovarian cancer, Ovarian Neuhauser eichner opitz syndrome, Neuhauser's anomaly, germ cell malignant tumor, Ovarioleukodystrophy, Oxalosis, Neural crest tumour, Neuroacanthocytosis, Neuroaxonal dys PAF, PAGOD syndrome, PAN, PANDAS, PAP. PAPA syn trophy, Neuroblastoma, Neurocutaneous melanosis, Neuro drome, PARC syndrome, PCA, PCARP, PCH with optic atro degeneration due to 3-hydroxyisobutyryl-CoA hydrolase phy, PCT, PDALS, PEHO syndrome, PEL, PELVIS syn deficiency, Neurodegeneration with brain iron accumulation drome, PFAPA syndrome, PFIC, PHACE syndrome, PIBIDS (NBIA), Neurodegenerative disease, Neuroectodermal syn syndrome, PJS, PLOSL, PMD, PNDM, POADS, POEMS drome, Neuroepithelioma, Neurofibromatosis, Neuroli syndrome, POF, POMC deficiency, PPA, PPHS, PPM-X, pomatosis, Neuromuscular junction disease, Neuromyelitis PPoma, PSEK, PSP, PTC-RCC, PTLAH, PTLD, Pachygyria, optica, Neuromyotonia, Neuropathy, Neutral Lipid Storage Pachyonychia, Pacman dysplasia, Paediatric Autoimmune Disease, Neutropaenia, Nevo syndrome, Nevoid hypermel Disorders Associated with Streptococcus infections, Paediat anosis, Nezelof syndrome, Nicolaides baraitser syndrome, ric Autoimmune Neuropsychiatric Disorders Associated with Niemann-Pick disease, Nievergelt syndrome, Niikawa Streptococcus infections, Paediatric granulomatous arthritis, Kuroki syndrome, Nijmegen breakage syndrome, Nivelon Paget disease, Pagon Stephan syndrome, Pai syndrome, Pal Nivelon-Mabille syndrome, Noack syndrome, Noble bass lister W syndrome, Pallister-Hall syndrome, Pallister-Killian sherman syndrome, Nocardiosis, Nodular lymphocyte pre syndrome, Palmer pagon syndrome, Palpebral disease, dominant Hodgkin lymphoma, Nodulosis-arthropathy-os Panayiotopoulos Syndrome, Pancreatic carcinoma, Pancre teolysis syndrome, Noma, Non-24-Hour Sleep-Wake syn atitis, Panner disease, Panniculitis, Panostotic fibrous dyspla drome. Non-DYT1 idiopathic torsion dystonia, Non sia, Papillo-renal syndrome, Papillomatosis, recurrent respi Hodgkin malignant lymphoma, Non-alcoholic ratory, Papillon-Leage-Psaume syndrome, Papillon-Lefevre Steatohepatitis, Non-amyloid monoclonal immunoglobulin syndrome, Papular and Sclerodermoid lichen myxedemato deposition disease, Non-giant cell granulomatous temporal Sus, Papularatrichia, Papular mucinosis of infancy, Paramyo arteritis with eosinophilia, Non-infectious uveitis affecting tonia, Paraneoplastic pemphigus, Paraneoplastic retinopathy, the posterior segment of the eye, Nonaka myopathy, NondyS Paraplegia, Parathyroid carcinoma, Parenchymatous liver germinomatous germ cell tumor, Noonan like contracture disease, Paris-Trousseau thrombocytopenia, Parkes-Weber myopathy hyperpyrexia, Noonan like syndrome, Noonan syndrome, Parkinson disease, Parkinsonism-dementia-ALS syndrome, Normomorphic sialidosis, Norrie disease, Norum complex, Paroxysmal cold haemoglobinuria, Paroxysmal disease, Nova syndrome, Novak syndrome, Nuclear cell exertion-induced dyskinesia, Paroxysmal ventricular fibrilla envelopathy, O donnell pappas syndrome, O'Doherty Syn tion, Parry-Romberg syndrome, Parsonage-Turner Syn drome, O'Sullivan-McLeod syndrome, OA-1, OCA, drome, Partial deep dermal and full thickness burns, Parting OCRL1, OFC syndrome, OFCD syndrome, OHSS, OLE ton amyloidosis, Partington disease, Partington-Anderson DAID, ONMR syndrome, OPPG, ORW 2, OSLAM syn syndrome, Partington-Mulley Syndrome, Parvovirus antena drome, OSMED, OTUDP syndrome, Obliterative portal ven tal infection, Pascuel castroViejo syndrome, Pashayan Syn opathy, Occlusive infantile arteriopathy, Occupational drome, Passwell-Goodman-Siprkowski syndrome, Patau allergic alveolitis, Ochoa syndrome, Ochronosis, Oculoskel syndrome, Patterned dystrophy of the retinal pigment epithe etal renal syndrome, Oculo-osteo-cutaneous syndrome, Ocu lium, Patterson pseudoleprechaunism syndrome, Patterson loectodermal syndrome, Oculogastrointestinal muscular dys Stevenson syndrome, Patterson-Lowry rhizomelic dysplasia, trophy, Oculomotor palsy, Oculomotor paralysis, Pauciarticular chronic arthritis, Pavone fiumara rizzo syn Oculopharyngodistal myopathy, Odontologic disease, Odon drome, Pearson syndrome, Peeling skin syndrome, Pelget tomatosis, Oerter-Friedman-Anderson syndrome, Oesoph Huer anomaly, Pelizaeus-Merzbacher brain sclerosis, Pella ageal atresia, Oguchi disease, Ohaha syndrome, Ohdo gra, Pemphigus, Pena-Shokeir syndrome, Pendred madokoro Sonoda syndrome, Ohtahara syndrome, Okamoto syndrome, Penta X syndrome, Pentosuria, Peptide metabo syndrome, Okihiro syndrome, Oligocone syndrome, Oligo lism disease, Peptidic growth factors deficiency, Perheentupa meganephronia, Oliver mcfarlane syndrome, Oliver Syn syndrome, Periarteritis nodosa, Pericardial defect diaphrag drome, Ollier disease, Olmsted syndrome, Omennsyndrome, matic hernia, Pericarditis, Perineurioma, Peripartum cardi Omodysplasia, Onat Syndrome. Onchocerciasis, Ondine Syn omyopathy, Peripheral T-cell lymphoma, Peripheral neur drome, Ondine-Hirschsprung disease, Onychodystrophy, opathy and optic atrophy, Peritoneal leiomyomatosis, Oochs syndrome, Ophtalmic ichthyosis, Ophtalmoplegia, Peritumoral oedema derived from brain tumours, Periven Opitz BBB/G syndrome, Opitz reynolds fitzgerald syndrome, tricular nodular heterotopia, Perlman syndrome, Pernicious Opitz-Caltabiano syndrome, Opitz-Frias syndrome, Oppen anaemia, Perniola krajewska carnevale syndrome, Peroxiso US 2010/0210567 A1 Aug. 19, 2010

mal beta-oxidation disease, Perrault syndrome, Persistent neuralgia, Pudendal neuropathy, Pulmonar arterioVeinous Mullerian duct syndrome, Peters anomaly, Peters-plus syn aneurysm, Pulmonary Langerhans cell histiocytosis, Pulmo drome, Petges-Clejat syndrome, Petit-Fryns syndrome, Petty nary alveolar microlithiasis, Pulmonary alveolar proteinosis, laxova wiedemann syndrome, Peutz-Jeghers syndrome, Pey Pulmonary aortic Stenosis, Pulmonary arterial hypertension, ronie syndrome, Pfeiffer mayer syndrome, Pfeiffer palm Pulmonary arterio-veinous fistula, Pulmonary artery hypo teller syndrome, Pfeiffer rockelein syndrome, Pfeiffer syn plasia, Pulmonary atresia, Pulmonary blastoma, Pulmonary drome, Pfeiffer-Kapferer syndrome, Pfeiffer-Singer-Zschi branch Stenosis, Pulmonary endometriosis, Pulmonary hae esche syndrome, Pfeiffer-Weber-Christian syndrome, Phaco mosiderosis, Pulmonary insufficiency, Pulmonary lym matosis, Phaeochromocytoma, Phagocyte function anomaly, phangiectasia, Pulmonary lymphangiomatosis, Pulmonary Phaver syndrome, Phelan-McDermid syndrome, Phenotypic nodular lymphoid hyperplasia, Pulmonary Supravalvular diarrhoea, Phenylketonuria, Phocomelia, Phytosterolemia, Stenosis, Pulmonary Surfactant protein anomalies, Pulmo Picardi-Lassueur-Little syndrome, Pick disease of brain, Pie nary valve agenesis (PVA), Pulmonary venoocclusive dis baldism, Pierre Robin sequence associated with branchial ease, Pulp stones, Pulpal dysplasia, Puretic syndrome, Purtilo archs anomalies, Pierre Robin sequence associated with col syndrome, Pycnodysostosis, Pyknoachondrogenesis, Pykno lagen diseases, Pigeon-breeder's lung disease, Pillay Syn lepsy, Pyle disease, Pyoderma gangrenosum, Pyomyositis, drome, Pilomatrixoma, Pilotto syndrome, Pinheiro freire Pyropoikilocytosis, Q fever, Qazi-Markouizos syndrome, maia miranda syndrome, Pinsky-Di George-Harley Syn Quattrin mcpherson syndrome, RAEB-1, RAPADILINO drome, Pitt-Hopkins syndrome, Pitt-Williams brachydactyl), syndrome, RB-ILD, RECQ2, RECQL3, RHS, Rabson-Men Pitt-rogers-danks syndrome, Pituitary adenoma, Pituitary denhall syndrome, Radiation syndromes, Radio renal Syn agenesis, Pituitary hormone deficiency, Pituitary lactotrophic drome, Raine syndrome, Rajab-Spranger syndrome, Ram adenoma, Pityriasis rubra pilaris, Piussan-Lenaerts-Mathieu bam-Hasharon syndrome, Rambaud galian syndrome, syndrome, Plasma cell tumour, Platelet function disease, Ramon syndrome, Ramos arroyo clark syndrome, Ramsay Platyspondylic dysplasia, Plectin deficiency, Pleomorphic hunt syndrome, Randall disease, Rapp-Hodgkin ectodermal liposarcoma, Pleuro-pulmonary blastoma, Pleuro-pulmonary dysplasia syndrome, Rapp-Hodgkin syndrome, Rasmussen endometriosis, Plott syndrome, Plum syndrome, Plummer johnsen thomsen syndrome, Rasmussen syndrome, Rathburn Vinson syndrome, Pneumoblastoma, Pneumocystosis, Pneu disease, Ray peterson Scott syndrome, Raynaud phenom monia caused by Pseudomonas Aeruginosa, Poikilo-der enon, Reardon-Baraitser syndrome, Reardon-Hall-Slaney matomyositis, Pollitt syndrome, Polyarteritis nodosa, syndrome, Recurrent hepatitis C virus induced liver disease Polyarthritis, Polycystic kidney disease, Polycystic liver dis in liver transplant recipients, Red cell aplasia, Refetoff syn ease, Polycystic ovarian disease, Polycythaemia, Polydac drome, Reflex sympathetic dystrophy syndrome, Refsum dis tyl), Polyepiphyseal dysplasia, Polymicrogyria, Polymorphic ease, Reginato-Schiapachasse syndrome, Reifenstein Syn catecholergic ventricular tachycardia, Polymyositis, Polyos drome, Reinhardt pfeiffer syndrome, Reiter's syndrome, totic fibrous dysplasia, Polyposis, Polysyndactyly-cardiac Renal adysplasia, Renal cell carcinoma, Renal dysplasia, malformation, Pompe disease, Popliteal web syndrome, Renal glucosuria, Renal hypertension, Renal hypoplasia, Porokeratosis, Porphyria, Portal hypertension, Portal vein Renal nutcracker syndrome, Renal tubular acidosis, Renal thrombosis, Post polio syndrome, Post transplantation graft tubular disorder, Renal-coloboma syndrome, Rendu-Osler 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 US 2010/0210567 A1 Aug. 19, 2010 24 drome, Rombo syndrome, Rommen mueller Sybert Syn dysmorphia syndrome (SDYS), Simpson-Golabi-Behmel drome, Rosai-Dorfman disease, Rosenberg lohr syndrome, syndrome, Sinding-Larsen-Johansson disease, Singh Rosenberg Chutorian syndrome, Rothmund-Thomson Syn chhaparwal dhanda syndrome, Singh-Williams-McAlister drome, Rotor syndrome, Roy maroteaux kremp syndrome, syndrome. Single ventricular septal defect, Singleton-Merten Rozin-Hertz-Goodman syndrome, Rubinstein-Taybi syn dysplasia, Singleton-Merten syndrome, Sino-auricular heart drome, Rudd-Klimek syndrome, Rudiger syndrome, Russell block, Sinus node disease and myopia, Sipple syndrome, Silver syndrome, Russell weaver bull syndrome, Rutherfurd Sirenomelia, Sitosterolemia, Situs inversus viscerum-cardi syndrome, Ruvalcaba syndrome, Ruvalcaba-Myhre-Smith opathy, Sjögren syndrome, Sjögren-Larsson syndrome, Skel syndrome, SADDAN, SANDO, SAPHO syndrome, SC pho etal dysplasia, Skeletal muscle disease, Skin collagen dis comelia, SCA, SCAN2, SCAR1, SCARF syndrome, SCASI, ease, Skin vascular disease, Sleep disorder, Sleeping SCD, SCID, SCLC, SE(M)D, SGBS, SGS, SHORT syn seekness, Sly disease, Small bowel adenocarcinoma, Small drome, SIADH, SIBIDS syndrome, SJS, SLK, SMD, SMEI, bowel leiomyosarcoma, Small non-cleaved cell lymphoma, SMMCI, SOD, SOLAMEN syndrome, SPG, SPONAS Smith martin dodd syndrome, Smith-Fineman-Myers syn TRIME dysplasia, SPS, SRP, SUNCT syndrome, Saal drome, Smith-Lemli-Opitz syndrome, Smith-Magenis syn Greenstein syndrome, Saccharopinuria, Sack-Barabas Syn drome, Sneddon syndrome, Sneddon-Wilkinson disease, drome, Saethre-Chotzen syndrome, Saito kuba tsuruta Snyder-Robinson syndrome, Soft tissue perineurioma, Soft syndrome, Sakati Syndrome, Sakati-Nyhan syndrome, tissue sarcomas, Sohval Soffer syndrome, Solitary plasmacy Sakati-Nyhan-Tisdale syndrome, Salcedo syndrome, Salla toma, Solomon syndrome, Somatotroph adenoma, Sommer disease, Salmonellosis, Salti salem syndrome, Sammartino hines syndrome, Sommer rathbun battles syndrome, Som decreccio syndrome, San Luis Valley syndrome, Sandhoff mer-Young-Wee-Frye syndrome, Sondheimer syndrome, disease, Sandifer syndrome, Sandrow syndrome, Sanfilippo Sonoda syndrome, Sorsby syndrome, Sorsby's fundus dys disease, Sanjad-Sakati Syndrome, Santavuori disease, San trophy, Sotos syndrome, Spastic paraplegia, Spellacy gibbs tos-Mateus-Leal syndrome, Sarcocystosis, Sarcoidosis, Sar watts syndrome, Spherophakia-brachymorphia, Sphingolipi cosinemia, Sarcosporidiosis, Satoyoshi syndrome, Say bar dosis, Spina bifida, Spinal atrophy, Spirillosis, Splenic mar ber hobbs syndrome, Say barber miller syndrome, Say field ginal Zone lymphoma, Spondylarthropathy, Spondylo camp coldwell syndrome, Say meyer syndrome, Scarring in glau todactyly syndrome, Spondylocostal dysostosis, coma filtration Surgical procedures, Schaap taylor baraitser Spondyloenchondrodysplasia, Spondyloepiphyseal dyspla syndrome, Scheie syndrome, Scheuermann disease, Schil sia, Spongy degeneration of central nervous system, Spongy bach-Rott syndrome, Schilder disease, Schimke syndrome, myocardium, Spontaneous pneumothorax familial type, Schimmelpenning syndrome, Schindler disease, Schinzel Sporotrichosis, Squamous cell carcinoma of head and neck, syndrome, Schisis association, Schistosomiasis, Schmidt St Louis encephalitis, Stalker chitayat Syndrome, Stampe syndrome, Schmitt gillenwater kelly syndrome, Schnecken Sorensen syndrome, Stapedo-Vestibular ankylosis, Staphylo becken dysplasia, Schnitzler syndrome, Schofer-Beetz-Bohl coccal necrotizing pneumonia, Staphylococcal Scarlet fever, syndrome, Scholte begeer Van essen syndrome, Schopf Staphylococcal toxic shock syndrome, Stargardt disease, Schulz-Passarge syndrome, Schwannomatosis, Schwartz Stark-Kaeser syndrome, Startle disease, Steatocystoma, Jampel syndrome, Scimitar syndrome, Scleroatrophic Syn Steele-Richardson-Olszewski disease, Stein-Leventhal syn drome, Scleroderma, Scleromyxedema, Sclerosing drome, Steinert myotonic dystrophy, Steinfeld syndrome, mediastinitis, Sclerosteosis, Scott syndrome, Scott-Bryant Stern-Lubinsky-Durrie syndrome, Stevens-Johnson syn Graham syndrome, Scott-Taor syndrome, Seaver cassidy drome, Stickler syndrome, Stiff person syndrome, Still dis syndrome, Sebastian syndrome, Seckel like syndrome, ease, Stimmler syndrome, Stoeling a de koomen davis Syn Seckel syndrome, Sedlackova Syndrome, Seemanova lesny drome, Stoll alembik finck syndrome, Stoll geraudel chauvin syndrome, Segawa syndrome, Seghers syndrome, Seitel syndrome, Stoll kieny dott syndrome, Stoll-Levy-Francfort berger disease, Selig-Benacerraf-Greene syndrome, Sellars syndrome, Stomach cancer, Stormorken-Sjaastad-Langslet Beighton syndrome, Sengers syndrome, Sengers-Hamel-Of syndrome, Stratton garcia young syndrome, Stratton parker ten syndrome, Senior syndrome, Senior-Boichis syndrome, syndrome, Streptobacillosis, Streptococcal toxic-shock Syn Senior-Loken syndrome, Sensenbrenner syndrome, Senter drome, Stress cardiomyopathie, Strumpell-Lorrain disease, syndrome, Sepsis, Septic phlebitis of the internal jugular Sturge-Weber syndrome, Stuve-Wiedemann dysplasia, Sub vein, Sequeiros sack syndrome, Servelle-Martorell syn cutaneous panniculitis-like T-cell lymphoma, Subpulmonary drome, Setleis syndrome, Severe closed traumatic brain Stenosis, Sucking/Swallowing disorder, Sudden infant death injury, Severe combined immunodeficiency T-B-. Severe syndrome, Sugarman syndrome, Sujansky-Leonard Syn combined immunodeficiency with hypereosinophilia, Severe drome, Sulfocysteinuria, Summerskill-Walshe-Tygstrup syn combined immunodeficiency with leukopenia, Severe pneu drome, Summitt syndrome, Supravalvar aortic Stenosis, mococcemia, Sezary's lymphoma, Shapiro syndrome, Susac syndrome, Sutton disease II, Sweet syndrome, Swyer Sharma kapoor ramji Syndrome, Sharp syndrome, Sheehan syndrome, Symphalangism, Syncopal paroxysmal tachycar syndrome, Shigellosis, Shokeir syndrome, Shone syndrome, dia, Syncopal tachyarythmia, Syndromatic diarrhea, Syn Short QT syndrome, Short bowel syndrome due to necrotiz ovialosarcoma, Synovitis, Synspondylism, Syntelencephaly, ing enterocolitis, Short bowel syndrome due to thrombosis, Syringocystadenoma papilliferum, Syringomyelia, Systemic Short bowel syndrome, Shprintzen omphalocele syndrome, capillary leak syndrome, Systemic lupus erythematosus, Sys Shprintzen-Goldberg syndrome, Shulman syndrome, temic mastocytosis, Systemic Scleroderma (systemic sclero Shwachman-diamond syndrome, Shy-drager syndrome, sis), Systemic vasculitis, T cell immunodeficiency, T-cell leu Sialidosis, Sickle cell anaemia, Sideroblastic anaemia, kaemia, T-cell chronic lymphocytic leukaemia, TAC, TAR Sidransky-Feinstein-Goodman syndrome, Siegler brewer syndrome, TCP, TDO syndrome, TEMF, TGA, TINU syn carey Syndrome, Silengo lerone pelizZo syndrome, Silence drome, TNF receptor 1 associated periodic syndrome, TOS, syndrome, Simosa penchasZadeh bustos syndrome, Simpson TRAPS syndrome, TTP, TTR amyloid cardiopathy, TTR US 2010/0210567 A1 Aug. 19, 2010 amyloid neuropathy, Tabatznik syndrome, Takatsuki Syn hire syndrome, Van Benthem-Driessen-Hanveld syndrome, drome, Takayasu arteritis, Takotsubo cardiomyopathy, Tang Van Bogaert disease, VanDerWoude syndrome, Vanbiervliet hsi ryu syndrome, Tangier disease, Tardive dyskinesia, Tarsal hendrickX Van ertbruggen syndrome, Van de berghe-De Tunnel syndrome, Tarui disease, Tauopathy, Taussig-Bing queker syndrome, Van den Bosch Syndrome, Van den ende syndrome, Tay Syndrome, Tay-Sachs disease, Taybi Syn brunner syndrome, Van der Knapp syndrome, Van goethem drome, Taybi-Linder syndrome, Teebi al Saleh hassoon syn syndrome, Van maldergem wetzburger verloes syndrome, drome, Teebi kaurah syndrome, Teebi naguib alawadi Syn Van regemorter pierquin Vamos syndrome, Varadi-Papp Syn drome, Teebi shaltout syndrome, Telangiectasia, drome, Vascular leukoencephalopathy, Vasculitis, Vasquez Telecanthus, Telfer Sugar jaeger syndrome, Temtamy Hurst-Sotos syndrome, Vasterbotten dystrophy, Vein of Galen Shalash syndrome, Ter Haar syndrome, Teratoma, Tetraame aneurysm, Venencie powell winkelmann syndrome, Ventricu lia, Tetralogy of Fallot, Thakker donnai syndrome, Thalas lar septal defect, Ventricular septal defect with aortic insuffi saemia syndrome, Thanatophoric dysplasia, Theodore's ciency, Verloes-Gillerot-Fryns syndrome, Verloes bourgui syndrome. Thiele syndrome. Thiemann disease. Thies-Reis gnon syndrome, Verloes david Syndrome, Verloes van syndrome, Thomas jewett raines syndrome, Thomas Syn maldergem marneffe Syndrome, Verloes-DepreZ Syndrome, drome, Thompson baraitser syndrome, Thomsen and Becker Verloove vanhorick brubakk syndrome, Verneuil disease, Vil disease, Thong douglas ferrante syndrome, Thoracic aortic joen winship syndrome, Viljoen-Kallis-Voges syndrome, Vil aneurysm and/or dissection, Thoracic outlet syndrome, Three joen-Smart syndrome, Viral hemorrhagic fever, Viral hepati M disease. Thromboangiitis obliterans, Thrombocytopaenia, tis, Viral vasculitis, Visceral neuropathy, Vitiligo, Thrombocytopenic purpura autoimmune, Thrombocytopenic Vitreoretinal degeneration, Vogt-Koyanagi-Harada disease, purpura idiopathic, Thrombocytosis, Thromboembolic pull Vohwinkel syndrome, Volcke-Soekarman syndrome, Von monary hypertension, Thrombotic disease of haematologic Gierke disease, Von Hippel-Lindau disease, Von Reckling origin, Thymic aplasia, Thymic carcinoma, Thyroid tumor, hausen disease, Von Voss-Cherstvoy syndrome, Von Will Tick-borne encephalitis, Tietze syndrome, Timothy syn ebrand disease, Von hippel anomaly, VSr syndrome, Vuopala drome, Tollner horst manzke syndrome, Tolosa-Hunt Syn disease, W syndrome, WAGR syndrome, WARBM1, WHIM drome, Tomaculous neuropathy, Tome brune fardeau Syn syndrome, WL syndrome, WT limb-blood syndrome, drome, Toni-Debré-Fanconi disease, Tonoki-Ohura-Niikawa Waaler-Aarskog syndrome, Waardenburg syndrome, syndrome, TORCH syndrome, Toriello syndrome, Toriello Waardenburg-Shah syndrome, Wagner disease, Waisman Carey syndrome, Toriello-Higgins-Miller syndrome, Tori syndrome, Waldenström macroglobulinemia, Waldmann dis ello-Lacassie-Droste syndrome, Torres ayber syndrome, ease, Walker-Dyson syndrome, Walker-Warburg syndrome, Tourette Syndrome, Townes-Brocks syndrome, Toxocariasis, Wallis cremin beighton syndrome, Wallis Zieff goldblatt syn Toxoplasma embryopathy, Toxoplasmosis, Tracheopathia drome, Warburg Micro syndrome, Warburg thomsen syn osteoplastica, Tranebaerg-Sveigaard syndrome, Transmis drome, Warburton-Anyane-Yeboa syndrome, Warman-Mul sible spongiform encephalopathies, Transposition of the liken-Hayward syndrome, Water-West syndrome, great arteries with pulmonary Stenosis, Transthyretinamyloid Waterhouse-Friedrickson syndrome, Watson syndrome, polyneuropathy, Treacher-Collins syndrome, Aspiration Weaver like syndrome, Weaver syndrome, Weaver-Williams pneumotitis requiring intubation and mechanical ventilation, syndrome, Weber-Christian disease (WCD), Weber-Christian Cardiogenic shock, Treft-Sanborn-Carey syndrome, Trench panniculitis, Webster deming syndrome, Wegener granulo fever, Trevor disease, Triatrial heart, Trichinosis, Tricho ony matosis, Weil syndrome, Weill-Marchesani syndrome, Weis chic dysplasia, Tricho-dento-Osseous syndrome, Tricho mann Netter Stuhl syndrome, Weissenbacher-Zweymuller hepato-enteric syndrome, Trichorhinophalangeal, Trichor syndrome, Wellesley-Carman-French syndrome, Wells syn rhexis nodosa syndrome, Trichothiodystrophy, Tricuspid drome, Wells-Jankovic syndrome, Werdnig-Hoffmann dis atresia, Triopia, Triple A syndrome, Triple H(HHH) syn ease, Wermer syndrome, Werner syndrome, Wernicke's drome, Triplo-X syndrome, Trisomy, Tritanopia, Trochlear encephalopathy, Wernicke-Korsakoff syndrome, West syn dysplasia, Tropical calcific chronic pancreatitis, Tropical drome, West-Nile encephalitis, Westerhof-Beemer-Cormane endomyocardial fibrosis, Truebburg bottani syndrome, Tsao syndrome, Western equine encephalomyelitis, Westphall dis Ellingson syndrome, Tsukahara-Kajii syndrome, Tsukuhara ease. Whelan syndrome. Whipple disease, Whistling face syndrome, Tsutsugamushi disease, Tsutsugamushi fever, syndrome, Whooping cough, Whyte-Murphy syndrome, Tuberculosis, Tuberous sclerosis, Tubular duplication of the Wieacker-Wolff syndrome, Wiedemann grosse dibbern syn oesophagus, Tubular dysplasia, Tubular renal disease—car drome, Wiedemann oldigs oppermann syndrome, Wiede diomyopathy, Tubulointerstitial nephritis and uveitis Syn mann-Beckwith syndrome, Wiedemann-Rautenstrauch syn drome, Tucker syndrome, Tuffli-Laxova syndrome, drome, Wildervanck syndrome, Wilkes Stevenson syndrome, Tularaemia, Tungiasis, Tungland-Bellman syndrome, Tunnel Wilkie-Taylor-Scambler syndrome, Willebrand disease, Subaortic Stenosis, Turcot syndrome, Turner syndrome, Willi-Prader syndrome, Williams syndrome, Williams Turner-Kieser syndrome, Twin.twin transfusion syndrome, Beuren syndrome, Wilms tumor, Wilson disease, Wilson Tylosis, ULD, UPDM, UPDP, USH, Uhl anomaly, Ulbright Turner syndrome, Winchester disease, Winkelman bethge hodes syndrome. Ulcerative colitis, Ulerythema ophryogen pfeiffer syndrome, Winkelmann's cytophagic panniculitis, esis, Ulick syndrome, Ullrich disease, Umbilical cord ulcer Winship viljoen leary syndrome, Winter harding hyde syn ation, Univentricular cardiopathy, Unverricht-Lundborg dis drome, Winter-Shortland-Temple syndrome, Wiskott-Ald ease, Upington disease, Upshaw-Schulman syndrome, rich syndrome, Wissler-Fanconi syndrome. Witkop syn Urbach-Wiethe disease, Urban-Rogers-Meyer syndrome, drome. Wittwer syndrome, Wolcott-Rallison syndrome, Urban-Schosser-Spohn syndrome, Uremic pruritus, Urrets Wolf-Hirschhorn syndrome, Wolff Zimmermann syndrome, Zavalia syndrome, Usher syndrome. Usual interstitial pneu Wolff-Parkinson-White syndrome, Wolfram syndrome, Wol monia (UIP), Uveitis, VIPoma, VMCM, VODI syndrome, man disease, Woodhouse sakati syndrome, Woods black nor VSD. VWS, Vagneur triolle ripert syndrome, Van Allen-My bury syndrome, Woods leversha rogers syndrome, Woods US 2010/0210567 A1 Aug. 19, 2010 26

Crouchman-Huson syndrome, Worster drought syndrome, of less than or equal to 32 weeks gestational age, Juvenile Worth syndrome, Wrinkly skin syndrome, Wyburn-Mason myelomonocytic leukaemia, Japanese encephalitis, Intestinal syndrome, XHIGM, XLAG syndrome, XMEA, XP, Xanthic graft-Versus-host disease, Indolent non-Hodgkin's lym urolithiasis, Xanthinuria, Xanthogranulomatous hypophysi phoma, Inborn errors in primary bile acid synthesis, Hyper tis, Xanthomatosis cerebrotendinous, Xerocytosis, Xero phenylalaninemia, Hypereosinophilic syndrome, Glioma, derma pigmentosum, Yellow fever, Yellow nail syndrome, High-grade dysplasia in Barrett's oesophagus, Herpes sim Yersiniosis, Yorifuji-Okuno syndrome, Yoshimura-takeshita plex virus stromal keratitis, Hereditary factor XIII deficiency, syndrom, Young maders syndrome, Young syndrome, Young Hepatocellular carcinoma, Hepatitis B re-infection following Hugues syndrome, Young-Simpson syndrome, Yunis-Varon liver transplantation, Hepatic veno-occlusive disease, Gram syndrome, ZASP-related myofibrillar myopathy, Zadik negative bacterial lung infection in cystic fibrosis, Gastric Barak-Levin Syndrome, Zellweger syndrome, Zellweger-like cancer, Gamma sarcoglycanopathy, Follicular lymphoma, syndrome, Zimmer phocomelia, Zimmerman laband Syn Familial adenomatous polyposis, Emphysema secondary to drome, Zinsser-Cole-Engman syndrome, Zlotogora-Ogur congenital alpha-1 antitrypsin deficiency, Duchenne muscu syndrome, Zlotogura-MartineZ Syndrome, Zollinger-Ellison lar dystrophy, Diffuse large B cell lymphoma, Diffuse alveo syndrome, Zori Stalker williams syndrome, Zunich-Kaye lar haemorrhage, Diarrhoea associated with intestinal syndrome, Zygomycosis, 2.8 dihydroxy-adenine urolithiasis, microSporidial infection, Cutaneous T-cell lymphoma, Cuta 2-aminoadipic aciduria, 2-hydroxyglutaricaciduria, 2-meth neous forms of lupus erythematosus, Cushing's syndrome ylbutyric aciduria, 3 hydroxyisobutyric acid uria, 3-hydroxy secondary to ectopic ACTH secretion, Corneal graft rejec 3-methylglutaric acid uria, 3-methylcrotonylglycinuria, tion, Congenital venous malformations, Congenital lym 3-methylglutaconic aciduria, 3C syndrome, 3M syndrome, phatic malformations, Congenital alpha-1 antitrypsin defi 4-hydroxybutyricaciduria, Visceral leishmaniasis, Vernal keratoconjunctivitis, UV-A and visible light-induced photo ciency, Congenital adrenal hyperplasia, Chronic pain, sensitivity disorders (chronic actinic dermatitis, cutaneous Cocaine poisoning, Chronic myeloid leukaemia, Chronic porphyrias, actinic prurigo and Solar urticaria), Uremic pru lymphocytic leukaemia, Chronic iron overload requiring che ritus, Tricyclic antidepressants poisoning, Traumatic spinal lation therapy, Chronic idiopathic myelofibrosis, Chronic cord injury, Renal cell carcinoma, Superficial bladder cancer, eosinophilic leukaemia and the hypereosinophilic syndrome, Staphylococcus aureus bacteraemia, Spinal cord injury, Cholangiocarcinoma, Charcot-Marie-Tooth disease type 1A, Spina bifida, Soft tissue sarcoma, Small cell lung cancer, Cardiogenic shock, Bronchopulmonary dysplasia in prema Sickle cell disease. Severe myoclonic epilepsy in infancy, ture neonates of less than 30 weeks of gestational age, B-cell Severe combined immunodeficiency (SCID). Severe closed chronic lymphocytic leukemia, Autoimmune uveitis, Atypi traumatic brain injury, Retinopathy of prematurity, Retinitis cal Haemolytic Uraemic Syndrome (ahUS) associated with pigmentosa, Respiratory distress syndrome in premature neo an inherited abnormality of the complement system, Aspira nates of less than 32 weeks of gestational age, Recurrent tion pneumonitis requiring intubation and mechanical venti hepatitis C virus induced liver disease in liver transplant lation, Aneurysmal Subarachnoid haemorrhage, Anaplastic recipients, Radiation proctitis, Pseudomonas aeruginosa thyroid cancer, Anal fistula, Acute sensorineural hearing loss lung infection in cystic fibrosis, Progressive myoclonic epi (acute acoustic trauma, Sudden deafness and Surgery induced lepsies, Primary malignant bone tumors, Primary apnoea of acoustic trauma), Acute peripheral arterial occlusion, Acute premature newborns, Post-transplant lymphoproliferative intermittent porphyria, Active phase of Peyronie's disease, disorders, Post-neonatal intracerebral haemorrhage, Post Acanthamoebakeratitis, A-mannosidosis, 5q spinal muscular transplantation graft dysfunction, Polycythemia Vera, Peritu atrophy, Cavopulmonary Anastomosis, Atrial Septal Defects moral oedema derived from brain tumors, Peripheral T-cell (ASD), Partial Anomalous Pulmonary Venous Return, Per lymphoma (nodal, other extranodal and leukaemic/dissemi sistent Common Atrio Ventricular Canal Endocardial Cush nated), Ductus arteriosus in premature neonates of less than 34 weeks of gestational age, Partial deep dermal and full ion Defect. Ostium Primum, Single Atrium, Patent Ductus thickness burns, Paroxysmal nocturnal haemoglobinuria, Arteriosus (PDA), Total Anomalous Pulmonary Venous Pancreatic cancer, Painful HIV-associated neuropathy, Ova Return, Ventricular Septal Defects (VSD), Pulmonary Valve rian cancer, Osteosarcoma, Orthostatic hypotension in Stenosis, Pulmonary Artery Stenosis and Stenosis of Pulmo patients with pure autonomic failure, Orthostatic hypotension nary Artery Branches, Pulmonary Atresia with Intact Ven in patients with multiple system atrophy, Ornithine-transcar tricular Septum, Congenital Mitral Valve Disease, Aortic Val bamylase deficiency, Oral mucositis in head and neck cancer Vular Stenosis and Congenital Aortic Valvular Regurgitation, patients undergoing radiation therapy, Oesophageal cancer, Supravalvular Aortic Stenosis, Transposition of the Great Non-traumatic osteonecrosis, Non-ketotic hyperglyci Arteries, Double Outlet Right Ventricle, Corrected Transpo naemia, Non-infectious uveitis affecting the posterior seg sition of the Great Arteries, Truncus Arteriosus, Aorto Pul ment of the eye, Non-24-hour sleep-wake disorders in blind monary Window, Tricuspid Atresia, Ebstein Anomaly, Mal people with no light perception, Neuroblastoma, Neovascular formations of the Vena Cava, Coarctation of the Aorta, Atresia glaucoma, Nephritic syndrome, Myelodysplastic syndromes, of Aortic Valve, Anomalies of the Aortic Arch, Anomalous Myasthenia gravis, Moderate and severe traumatic brain Origin of the Right Subclavian Artery with Coarctation of the injury, Metachromatic leukodystrophy, Medullary thyroid Aorta, Idiopathic Dilatation of the Pulmonary Artery, Left carcinoma, Mastocytosis, Mantle cell lymphoma, Malignant Pulmonary Artery Arising from Right Pulmonary Artery, melanoma, Malignant gastrointestinal stromal tumors, Mal Dextrocardia-Situs Inversus Totalis, Association of Heart absorption due to exocrine pancreatic enzyme insufficiency, Malformations with Asplenia, Malformations of the Vena Low flow priapism, Lipoprotein lipase deficiency, Ligneous Cava, Congenital Coronary Artery Arterio-Venous Fistula, conjunctivitis, Leber's hereditary optic neuropathy, Leber's Abnormal Origin of the Coronary Arteries, Aneurysm of the congenital amaurosis, Late onset sepsis in premature infants Sinus of Valsalva (Aortic Sinus Aneurysm), Endocardial US 2010/0210567 A1 Aug. 19, 2010 27

Fibroelastosis, Idiopathic Hypertrophic Subaortic Stenosis acid, D-o-tolyltartaric acid, tartronic acid, C-toluic acid, (o. (IHSS), Mitral Valve Prolapse-Barlow's Syndrome, Hypo m, p)-toluic acid, naphthylamine Sulfonic acid, and other plastic Left Heart. mineral or carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form Pharmaceutical Compositions with a sufficient amount of the desired acid to produce a salt 0144. Still another aspect of the present invention relates in the conventional manner. to the use of the peptide according to claim 1 as an active 0151. The pharmaceutical compositions according to the ingredient, together with at least one pharmaceutically present invention will typically be administered together with acceptable carrier, excipient and/or diluents for the manufac suitable carrier materials selected with respect to the intended ture of a pharmaceutical composition for the treatment and/or form of administration, i.e. for oral administration in the form prophylaxis of cancer, an autoimmune disease, a fibrotic dis of tablets, capsules (either solid filled, semi-solid filled or ease, an inflammatory disease, a neurodegenerative disease, liquid filled), powders for constitution, aerosol preparations an infectious disease, a lung disease, a heart and vascular consistent with conventional pharmaceutical practices. Other disease or a metabolic disease or any other disease disclosed Suitable formulations are gels, elixirs, dispersible granules, herein. syrups, Suspensions, creams, lotions, solutions, emulsions, 0145 Such pharmaceutical compositions comprise the Suspensions, dispersions, and the like. Suitable dosage forms peptide as an active ingredient, together with at least one for Sustained release include tablets having layers of varying pharmaceutically acceptable carrier, excipient, binders, dis disintegration rates or controlled release polymeric matrices integrates, glidents, diluents, lubricants, coloring agents, impregnated with the active components and shaped in tablet Sweetening agents, flavoring agents, preservatives or the like. form or capsules containing such impregnated or encapsu The pharmaceutical compositions of the present invention lated porous polymeric matrices. The pharmaceutical com can be prepared in a conventional Solid or liquid carrier or positions may be comprised of 5 to 95% by weight of the diluents and a conventional pharmaceutically-made adjuvant peptide. at Suitable dosage level in a known way. 0152. As pharmaceutically acceptable carrier, excipient 0146 Preferably the peptide is suitable for intravenous and/or diluents can be used lactose, starch, Sucrose, cellulose, administration or suitable for oral administration or suitable magnesium Stearate, dicalcium phosphate, calcium sulfate, for administration by inhalation. talc, mannitol, ethyl alcohol (liquid filled capsules). 0147 Administration forms include, for example, pills, 0153 Suitable binders include starch, gelatin, natural sug tablets, film tablets, coated tablets, capsules, liposomal for ars, corn Sweeteners, natural and synthetic gums such as mulations, micro- and nano-formulations, powders and acacia, Sodium alginate, carboxymethyl-cellulose, polyethyl deposits. Furthermore, the present invention also includes ene glycol and waxes. Among the lubricants that may be pharmaceutical preparations for parenteral application, mentioned for use in these dosage forms, boric acid, sodium including dermal, intradermal, intragastral, intracutan, intra benzoate, Sodium acetate, Sodium chloride, and the like. Dis Vasal, intravenous, intramuscular, intraperitoneal, intranasal, integrants include starch, methylcellulose, guar gum and the intravaginal, intrabuccal, percutan, rectal, Subcutaneous, Sub like. Sweetening and flavoring agents and preservatives may lingual, topical, or transdermal application, which prepara also be included where appropriate. Some of the terms noted tions in addition to typical vehicles and/or diluents contain the above, namely disintegrants, diluents, lubricants, binders and peptide according to the present invention. the like, are discussed in more detail below. 0148. The present invention also includes the mammalian 0154 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 014.9 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. 0150. The peptide of the invention forms pharmaceuti 0155 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 0156 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, 0157 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 0158. The peptide of the present invention may also be delic acid, hydrogen-benzenesulfonic acid, picric acid, adipic deliverable transdermally. The transdermal compositions US 2010/0210567 A1 Aug. 19, 2010 28 may take the form of creams, lotions, aerosols and/or emul 0.165 Powders for constitution refer to powder blends sions and can be included in a transdermal patch of the matrix containing the active ingredients and Suitable diluents which or reservoir type as are conventional in the art for this purpose. can be suspended in water orjuices. One example for Such an 0159. The transdermal formulation of the peptide of the oral administration form for newborns, toddlers and/or invention is understood to increase the bioavailability of said infants is a human breast milk substitute which is produced peptide into the circulating blood. One problem in the admin from milk powder and milk whey powder, optionally and istration of peptides is the loss of bioactivity due to the for partially substituted with lactose. mation of insolubles in aqueous environments or due to deg 0166 Human breast milk is a complex fluid, rich in nutri radation. Therefore stabilization of peptides for maintaining ents and in non-nutritional bioactive components. It contains their fluidity and maintaining their biological activity upon all of the nutrients needed by the newborn baby. These administration to the patients in need thereof needs to be include the metabolic components (fat, protein, and carbohy achieved. drates), water, and the raw materials for tissue growth and 0160 Prior efforts to provide active agents for medication development. Such as fatty acids, amino acids, minerals, Vita include incorporating the medication in a polymeric matrix mins, and trace elements. whereby the active ingredient is released into the systemic (0167 More than 98% of the fat in is in the form of trig circulation. Known Sustained-release delivery means of lycerides. Oleic acid and palmitic acid are the most abundant active agents are disclosed, for example, in U.S. Pat. No. fatty acids in breastmilk triglycerides, with comparatively 4,235,988, U.S. Pat. No. 4,188,373, U.S. Pat. No. 4,100,271, U.S. Pat. No. 447471, U.S. Pat. No. 4,474,752, U.S. Pat. No. high proportions of the essential fatty acids, and linolenic 4,474,753, or U.S. Pat. No. 4,478,822 relating to polymeric acid, followed by long-chain polyunsaturated fatty acids, pharmaceutical vehicles for delivery of pharmaceutically Such as arachidonic acid and docosahexaenoic acid. These active chemical materials to mucous membranes. The phar long-chain fatty acids are constituents of brain and neural maceutical carriers are aqueous Solutions of certain polyoxy tissue and are needed in early life for mental and visual ethylene-polyoxypropylene condensates. These polymeric development. The lipid component of breast milk is the trans pharmaceutical vehicles are described as providing for port vehicle for fat-soluble micronutrients such as prostag increased drug absorbtion by the mucous membrane and pro landins and vitamins A, D, E, and K. longed drug action by a factor of two or mare. The Substitu 0168 Proteins account for approximately 75% of the ents are block copolymers of polyoxypropylene and polyoxy nitrogen-containing compounds in breast milk. Non-protein ethylene used for stabilization of drugs such as insulin. nitrogen Substances include urea, nucleotides, peptides, free 0161 Aqueous solutions of polyoxyethylene-polyox amino acids, and DNA. The proteins of breast milk can be ypropylene block copolymers (poloxamers) are useful as sta divided into two categories: micellar caseins and aqueous bilizers for the peptide. Aside from serving as a stabilizer for whey proteins, present in the ratio of about 40:60. Casein the peptide, poloxamers provide excellent vehicles for the forms micelles of relatively small volume and produces a soft, delivery of the peptide, and they are physiologically accept flocculent curd in the infant’s stomach. The major whey pro able. Poloxamers, also known by the trade name Pluronics teins are lactalbumin, lactoferrin, secretory IgA, and serum (e.g. Pluronic F127, Pluronic P85, Pluronic F68) have surfac albumin, with a large number of other proteins and peptides tant properties that make them useful in industrial applica present in Smaller amounts. tions. Among other things, they can be used to increase the 0169. The principal carbohydrate is lactose, a disaccha water solubility of hydrophobic, oily substances or otherwise ride produced in the mammary epithelial cell from glucose by increase the miscibility of two substances with different a reaction involving lactalbumin. hydrophobicities. For this reason, these polymers are com 0170 In addition to the nutritional components, breast monly used in industrial applications, cosmetics, and phar milk contains a wealth of bioactive components that have maceuticals. They have also been used as model systems for beneficial non-nutritional functions. These include a wide drug delivery applications. In situ gelation of pharmaceutical range of specific and non-specific antimicrobial factors; compositions based on poloxamer that are biologically trig cytokines and anti-inflammatory Substances; and hormones, gered are known in the art (e.g. U.S. Pat. No. 5.256,396), growth modulators, and digestive enzymes (Table 1), many of describing compositions containing poloxamer 407 and which have multiple activities. These components may be of water at specified concentrations. particular importance for young infants because of the imma 0162 The term capsule refers to a special container or turity of the host defense and digestive systems early in life. enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing com TABLE 1 positions comprising the active ingredients. Hard shell cap sules are typically made of blends of relatively high gel Examples of the non-nutritional components of breast milk strength bone and pork skin gelatins. The capsule itself may contain Small amounts of dyes, opaquing agents, plasticizers Antimicrobial factors and preservatives. Secretory IgA, IgM, IgG lactoferrin 0163 Tablet means compressed or molded solid dosage lysozyme form containing the active ingredients with Suitable diluents. complement C3 The tablet can be prepared by compression of mixtures or leucocytes granulations obtained by wet granulation, dry granulation or bifidus factor lipids and fatty acids by compaction well known to a person skilled in the art. antiviral mucins, GAGs 0164 Oral gels refers to the active ingredients dispersed or oligosaccharides solubilized in a hydrophilic semi-solid matrix. US 2010/0210567 A1 Aug. 19, 2010 29

can convert milk concentrate into a powder while still keeping TABLE 1-continued the valuable properties of the milk. The principle of all spray dryers is to transform the concentrate into many Small drop Examples of the non-nutritional components of breast milk lets which are then exposed to a fast current of hot air. Cytokines and anti-inflammatory Because of the very large surface area of the droplets, the factors water evaporates almost instantaneously and the droplets are transformed into powderparticles. tumor necrosis factor interleukins 0.174 Powdered milk is a powder made from dried milk interferons solids. Powdered milk has a far longer shelf life than liquid prostaglandins milk and does not need to be refrigerated due to its low antichymotrypsin moisture content. antitrypsin platelet-activating factor 0.175. Instant milk powder is produced by partially rehy Hormones drating the dried milk powder particles causing them to become Sticky and agglomerate. The water is then removed feedback inhibitor of lactation (FIL) insulin by drying resulting in an increased amount of air incorporated prolactin between the powder particles. thyroid hormones 0176 Milk powder manufacture is a process carried out on corticosteroids a large scale. It involves the gentle removal of water, while ACTH Oxytocin retaining all the desirable natural properties of the milk like calcitonin colour, flavour, solubility, nutritional value. parathyroid hormone 0177 Milk powder process includes spray drying, fluid erythropoietin bed processing, extraction, evaporation and freeze drying. Growth factors Other processes are freeze concentration, filteration, and epidermal (EGF) homogenisation. nerve (NGF) 0.178 The artificial mother milk formulations or mother insulin-like (IGF) transforming (TGF) milk substitutes of the present invention are preferably pre aurine pared by adding to a mother milk formulation including com polyamines mercially available mother milk formulations especially in Digestive enzymes powerform the peptide of the present invention. The peptide amylase is preferably added in an amount of 3-100 ug peptide or per bile acid-stimulating esterase 100 ml (commercially available) mother milk formulation, bile acid-stimulating lipases more preferably in an amount of 5-70 g/100 ml and most ipoprotein lipase preferably in an amount of 10-40 ug/100 ml mother milk Transporters formulation. actoferrin (Fe) 0179 Suitable diluents are substances that usually make olate binder up the major portion of the composition or dosage form. cobalamin binder gF binder Suitable diluents include Sugars such as lactose, Sucrose, hyroxine binder mannitol and sorbitol, starches derived from wheat, corn rice corticosteroid binder and potato, and celluloses such as microcrystalline cellulose. The amount of diluents in the composition can range from about 5 to about 95% by weight of the total composition, 0171 Besides breast milk, infant formula is the only other preferably from about 25 to about 75%, more preferably from infant milk which the medical community considers nutri about 30 to about 60% by weight, and most preferably from tionally acceptable for infants under the age of one year. about 40 to 50% by weight. Cow's milk is not recommended because of its high protein 0180. The term disintegrants refers to materials added to and electrolyte (salt) content which may harm infant's imma the composition to help it break apart (disintegrate) and ture kidneys. The nutrient content of infant formula should release the medicaments. Suitable disintegrants include comprise: Protein, Fat, Linoleic acid, Vitamins: A, C, D, E, K, starches, “cold water soluble” modified starches such as thiamin (B1), riboflavin (B2), B6, B12, Niacin, Folic acid, Sodium carboxymethyl starch, natural and synthetic gums Pantothenic acid, Calcium, Metals: magnesium, iron, Zinc, Such as locust bean, karaya, guar, tragacanth and agar, cellu manganese, copper, Phosphorus, Iodine, Sodium chloride, lose derivatives such as methylcellulose and Sodium car Potassium chloride. In addition, formulas not made with boxymethylcellulose, microcrystalline celluloses and cross cow’s milk must include biotin, choline, and inositol. linked microcrystalline celluloses such as sodium Hypoallergenic formulas reduce the likelihood of certain croScarmellose, alginates such as alginic acid and sodium medical complications in babies with specific health prob alginate, clays such as bentonites, and effervescent mixtures. lems. Baby formula can be synthesized from raw amino acids. The amount of disintegrant in the composition can range from 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. preferably from about 3 to 20% by weight of the composition, 0172 Powder blends containing the active ingredients and and most preferably from about 5 to about 10% by weight. Suitable diluents which can be suspended in water or juices 0181 Binders characterize substances that bind or “glue' can be produced by spray drying. powders together and make them cohesive by forming gran 0173 Spray drying has been found the most suitable pro ules, thus serving as the “adhesive' in the formulation. Bind cess for removing the last part of the water, since spray drying ers add cohesive strength already available in the diluents or US 2010/0210567 A1 Aug. 19, 2010 30 bulking agent. Suitable binders include Sugars such as shaped multiparticulates that are difficult to process into dos Sucrose, starches derived from wheat, corn rice and potato; age forms. This problem is solved by e.g. WO 2007 104173 natural gums such as acacia, gelatin and tragacanth; deriva where the particles consist of a poloxamer, a resin, and/or a tives of seaweed such as alginic acid, Sodium alginate and tocopherol, creating together with the medicament (e.g. insu ammonium calcium alginate; cellulosic materials such as lin) micelles. Micelleformation is essential for the absorption methylcellulose and sodium carboxymethylcellulose and ofmany nutrients within the human body. Bile salts formed in hydroxypropyl-methylcellulose; polyvinylpyrrolidone; and the liver and secreted by the gallbladder allow micelles of inorganics Such as magnesium aluminum silicate. The fatty acids to form. This allows the absorption of complicated amount of binder in the composition can range from about 1 lipids and lipid soluble vitamins within the micelle by the to 30% by weight of the composition, preferably from about Small intestine. Micelles are approximately spherical in 2 to about 20% by weight of the composition, more preferably shape. Preferably, peptide of the invention are formulated from about 3 to about 10% by weight, even more preferably with apoloxameranda resin to form micelles suitable for oral from about 3 to about 6% by weight. administration to patients in need of the medicament. 0182 Lubricant refers to a substance added to the dosage 0187 Liquid form preparations include solutions, suspen form to enable the tablet, granules, etc. after it has been sions and emulsions. As an example may be mentioned water compressed, to release from the mold or die by reducing or water-propylene glycol solutions for parenteral injections friction or wear. Suitable lubricants include metallic stearates or addition of Sweeteners and opacifiers for oral Solutions, Such as magnesium Stearate, calcium Stearate or potassium Suspensions and emulsions. Liquid form preparations may Stearate, Stearic acid; high melting point waxes; and water also include solutions for intranasal administration. soluble lubricants such as sodium chloride, Sodium benzoate, 0188 Other preferred pharmaceutical compositions are Sodium acetate, Sodium oleate, polyethylene glycols and dil buffered solutions. The term buffer, buffer system, buffer leucine. Lubricants are usually added at the very last step solution and buffered solution, when used with reference to before compression, since they must be present on the Sur hydrogen-ion concentration or pH, refers to the ability of a faces of the granules and in between them and the parts of the system, particularly an aqueous Solution, to resist a change of tablet press. The amount of lubricant in the composition can pH on adding acid or alkali, or on dilution with a solvent. range from about 0.05 to about 15% by weight of the com Preferred buffer systems can be selected from the group con position, preferably 0.2 to about 5% by weight of the com sisting of formate (pKa=3.75), lactate (pKa=3.86), benzoic position, more preferably from about 0.3 to about 3%, and acid (pKa=4.2) oxalate (pKa=4.29), fumarate (pKa=4.38), most preferably from about 0.3 to about 1.5% by weight of the aniline (pKa=4.63), acetate buffer (pKa=4.76), citrate buffer composition. (pKa2=4.76, pKa2=6.4), glutamate buffer (pKa=4.3), phos 0183 Glidents are materials that prevent caking and phate buffer (pKa=7.20), succinate (pKa1 =4.93: pKa2=5. improve the flow characteristics of granulations, so that flow 62), pyridine (pKa=5.23), phthalate (pKa=5.41); histidine is Smooth and uniform. Suitable glidents include silicon diox (pKa=6.04), MES (2-(N-morpholino)ethanesulphonic acid; ide and talc. The amount of glident in the composition can pKa=6.15); maleic acid (pKa=6.26); cacodylate (dimethy range from about 0.01 to 10% by weight of the composition, larsinate, pKa=6.27), carbonic acid (pKa=6.35), ADA (N-(2- preferably 0.1% to about 7% by weight of the total composi acetamido)imino-diacetic acid (pKa=6.62); PIPES (4-pip tion, more preferably from about 0.2 to 5% by weight, and erazinebis-(ethanesulfonic acid; BIS-TRIS-propane (1,3-bis most preferably from about 0.5 to about 2% by weight. tris(hydroxymethyl)methylamino-propane), pKa=6.80), 0184 Coloring agents are excipients that provide colora ethylendiamine (pKa=6.85), ACES 2-(2-amino-2-oxoethyl) tion to the composition or the dosage form. Such excipients aminoethanesulphonic acid; pKa=6.9), imidazole (pKa=6. can include food grade dyes and food grade dyes adsorbed 95), MOPS (3-(N-morphin)-propansulfonic acid: pKa=7. onto a Suitable adsorbent such as clay or aluminum oxide. The 20), diethylmalonic acid (pKa=7.2), TES (2-tris amount of the coloring agent can vary from about 0.01 to 10% (hydroxymethyl)methylamino ethanesulphonic acid; by weight of the composition, preferably from about 0.05 to pKa=7.50) and HEPES (N-2-hydroxylethylpiperazin-N'-2- 6% by weight, more preferably from about 0.1 to about 4% by ethansulfonic acid; pKa=7.55) buffers or other buffers having weight of the composition, and most preferably from about a pKa between 3.8 to 7.7. 0.1 to about 1%. (0189 Preferred is the group of carboxylic acid buffers 0185. The peptide of the invention can be used to form Such as acetate and carboxylic diacid buffers such as fuma multiparticulates, discrete particles, well known dosage rate, tartrate and phthalate and carboxylic triacid buffers such forms, whose totality represents the intended therapeutically as citrate. Another group of preferred buffers is represented useful dose of a drug. When taken orally, multiparticulates by inorganic buffers such as Sulfate, borate, carbonate, generally disperse freely in the gastrointestinal tract, and oxalate, calcium hydroxyde and phosphate buffers. Another maximize absorption. A specific example is described in U.S. group of preferred buffers are nitrogen containing buffers Pat. No. 6,068,859, disclosing multiparticulates that provide Such as imidazole, diethylenediamine, and piperazine. controlled release of azithromycin. Another advantage of the 0190. Also preferred are sulfonic acid buffers such as TES, multiparticulates is the improved stability of the drug. The HEPES, ACES, PIPES, (2-hydroxy-1,1-bis(hydroxym poloxamer component of the multiparticulate is very inert, ethyl)ethyl)amino-1-propanesulfonic acid (TAPS), 4-(2-hy thus minimizing degradation of the drug. droxyethyl)piperazine-1-propanesulfonic acid (EPPS), 0186. 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 0191 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). US 2010/0210567 A1 Aug. 19, 2010

0.192 Preferred are also amino acid buffers such as gly of from about 30 to 120 mM) or an acetate buffer (preferably cine, alanine, Valine, leucine, isoleucine, serine, threonine, at a final formulation concentration of about 20 to 200 mM) or phenylalanine, tyrosine, tryptophane, lysine, arginine, histi a phosphate buffer (preferably at a final formulation concen dine, aspartate, glutamate, asparagine, glutamine, cysteine, tration of about 20 to 200 mM). methionine, proline, 4-hydroxyproline, N.N.N-trimethyll 0196) Techniques for the formulation and administration ysine, 3-methylhistidine, 5-hydroxylysine, O-phosphoserine, of the peptide of the present invention may be found in “Rem Y-carboxyglutamate, e-N-acetyllysine, ()-N-methylarginine, ington's Pharmaceutical Sciences’ Mack Publishing Co., citruline, ornithine and derivatives thereof. Easton Pa. A Suitable composition comprising the peptide mentioned herein may be a solution of the peptide in a Suit TABLE 2 able liquid pharmaceutical carrier or any other formulation Such as tablets, pills, film tablets, coated tablets, dragees, Also preferred are the following buffers: capsules, powders and deposits, gels, syrups, slurries, Suspen sions, emulsions, and the like. effective pH range pKa 25°C. buffer 0.197 A particularly preferred pharmaceutical composi 2.7-4.2 340 malate (pK1) tion is a lyophilised (freeze-dried) preparation (lyophilisate) 3.0-4.5 3.75 formate 3.0-6.2 4.76 citrate (pK2) suitable for administration by inhalation or for intravenous 3.2-52 4.21 Succinate (pK1) administration. To prepare the preferred lyophilised prepara 36-56 4.76 acetate tion the peptides of the invention are solubilised in a 4 to 5% 38-56 4.87 propionate 4.0-6.0 S.13 malate (pK2) (w/v) mannitol solution and the solution is then lyophilised. 4.9-5.9 5.23 pyridine The mannitol Solution can also be prepared in a Suitable 5.0-6.O 5.33 piperazine (pK1) buffer solution as described above. 5.0-74 6.27 cacodylate 0198 Further examples of suitable cryo-flyoprotectants S.S.-6.5 5.64 Succinate (pK2) S.S.-6.7 6.10 MES (otherwise referred to as bulking agents or stabilizers) include 5.5-7.2 6.40 citrate (pK3) thiol-free albumin, immunoglobulins, polyalkyleneoxides 5.5-7.2 6.24 maleate (pK2) (e.g. PEG, polypropylene glycols), trehalose, glucose, SS-74 1.70, 6.04, 9.09 histidine Sucrose, Sorbitol, dextran, maltose, raffinose, stachyose and 5.8-7.2 6.46 bis-tris 58-8.0 7.20 phosphate (pK2) other saccharides (cf. for instance WO97/29782), while man 6.O-12.O 9.SO ethanolamine nitol is used preferably. These can be used in conventional 6.O-7.2 6.59 ADA amounts in conventional lyophilization techniques. Methods 6.0-8.0 6.35 carbonate (pK1) of lyophilisation are well known in the art of preparing phar 6.1-7.5 6.78 ACES maceutical formulations. 6.1-7.5 6.76 PIPES 6.2-7.6 6.87 MOPSO 0199 For administration by inhalation the particle diam 6.2-7.8 6.95 imidazole eter of the lyophilised preparation is preferably between 2 to 6.3-9.5 6.80, 9.00 BIS-TRIS propane 5 Lim, more preferably between 3 to 4 lum. The lyophilised 6.4-7.8 7.09 BES preparation is particularly suitable for administration using 6.5-7.9 7.14 MOPS 6.8-82 7.48 HEPES an inhalator, for example the OPTINEB(R) or VENTA-NEB(R) 6.8-82 740 TES inhalator (NEBU-TEC, Elsenfeld, Germany). The lyophi 6.9-8.3 7.60 MOBS lised product can be rehydrated insterile distilled water or any 7.0-8.2 7.52 DIPSO 7.0-8.2 7.61 TAPSO other suitable liquid for inhalation administration. 7.0-8.3 7.76 triethanolamine (TEA) 0200 Alternatively for intravenous administration the 7.0-9.0 0.91, 2.10, 6.70, 9.32 pyrophosphate lyophilised product can be rehydrated insterile distilled water 7.1-8.5 7.85 HEPPSO or any other Suitable liquid for intravenous administration. 7.2-8.5 7.78 POPSO 0201 After rehydration for administration in sterile dis tilled water or another suitable liquid the lyophilised prepa (0193 Preferred are the buffers having an effective pH ration should have the approximate physiological osmolality range of from 2.7 to 8.5, and more preferred of from 3.8 to 7.7. of the target tissue for the rehydrated peptide preparation i.e. 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. 0194 Most preferred are buffers suitable for pharmaceu 0202 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 0203 Still another aspect of the present invention relates carboxylic diacid buffers as well as carboxylic triacid buffers. to the use of disclosed peptides as a dietary Supplement. That Of course also combinations of buffers, especially of the dietary Supplement is preferably for oral administration and buffers mentioned herein are useful for the present invention. especially but not limited to administration to newborns, tod 0.195 Some suitable pharmaceutical buffers are a citrate dlers, and/or infants. A dietary Supplement is intended to buffer (preferably at a final formulation concentration of from supplement the diet. The “dietary ingredients’ in these prod about 20 to 200 mM, more preferably at a final concentration ucts may in addition include: Vitamins, minerals, herbs or US 2010/0210567 A1 Aug. 19, 2010 32 other botanicals, amino acids, and Substances Such as that both the known drug and the peptide will have a thera enzymes, organ tissues, glandulars, and metabolites. Dietary peutic effect. In some cases this therapeutic effect will be Supplements may be manufactured in forms such as tablets, synergistic. Such concomitant administration can involve capsules, softgels, gelcaps, liquids, or powders. concurrent (i.e. at the same time), prior, or Subsequent admin istration of the drug with respect to the administration of the Method of Treatment peptide of the present invention. A person of ordinary skill in 0204 Another aspect of the present invention relates to a the art would have no difficulty determining the appropriate method of prophylaxis and/or treatment of cancer, an autoim timing, sequence and dosages of administration for particular mune disease, a fibrotic disease, an inflammatory disease, a drugs and peptide of the present invention. neurodegenerative disease, an infectious disease, a lung dis ease, a heart and vascular disease or a metabolic disease or Definition of Peptide Activity any other disease disclosed hereinan infectious disease, an autoimmune disease, a fibrotic disease, an inflammatory dis 0211 A peptide is deemed to have therapeutic activity if it ease, a neurodegenerative disease, or a heart and vascular demonstrated any one of the following activities listed ina) to disease comprising administering to a patient in need thereof g). a pharmaceutical composition comprising the peptide Thr a) The peptide could inhibit the activity of an over active Lys-Pro-Arg-OH in a therapeutically effective amount effec biological pathway. tive to treat the afore-mentioned disease. according to the present invention. b) The peptide could inhibit the production of an over pro 0205 Accordingly, the terms “prophylaxis' or “treat duced biological molecule. ment includes the administration of the peptide of the c) The peptide could inhibit the activity of an over produced present invention to prevent, inhibit, or arrest the symptoms biological molecule. of an infectious disease, an autoimmune disease, a fibrotic d) The peptide could increase the activity of an under active disease, an inflammatory disease, a neurodegenerative dis biological pathway. ease, or a heart and vascular disease. In some instances, e) The peptide could increase the production of an under treatment with the peptides of the present invention will be produced biological molecule. done in combination with other protective compounds to prevent, inhibit, or arrest the symptoms of an infectious dis f) The peptide could mimic the activity of an under produced ease, an autoimmune disease, a fibrotic disease, an inflam biological molecule. matory disease, a neurodegenerative disease, or a heart and g) The peptide could prevent, inhibit, or arrest the symptoms vascular disease. and/or progression of cancer, an infectious disease, an 0206. The term “active agent” or “therapeutic agent’ as autoimmune disease, a fibrotic disease, an inflammatory dis used herein refers to an agent that can prevent, inhibit, or ease, a neurodegenerative disease, or a heart and vascular arrest the symptoms and/or progression of an infectious, an disease or any other disease disclosed herein. autoimmune disease, a fibrotic disease, an inflammatory dis 0212. As used herein “inhibition' is defined as a reduction ease, a neurodegenerative disease, or a heart and vascular of the activity or production of a biological pathway or mol disease or any other disease disclosed herein. ecule activity of between 10 to 100%. More preferably the 0207. The term “therapeutic effect” as used herein, refers reduction of the activity or production of a biological pathway to the effective provision of protection effects to prevent, or molecule activity is between 25 to 100%. Even more pref inhibit, or arrest the symptoms and/or progression of an infec erably the reduction of the activity or production of a biologi tious, an autoimmune disease, a fibrotic disease, an inflam cal pathway or molecule activity is between 50 to 100%. matory disease, a neurodegenerative disease, or a heart and 0213. As used herein “increase' is defined as an increase vascular disease. of the activity or production of a biological pathway or mol 0208. The term “a therapeutically effective amount’ as ecule of between 10 to 100%. More preferably the increase of used herein means a sufficient amount of the peptide of the the activity or production of a biological pathway or molecule invention to produce atherapeutic effect, as defined above, in activity is between 25 to 100%. Even more preferably the a subject or patient in need of treatment. increase of the activity or production of a biological pathway 0209. The terms “subject” or “patient” are used herein or molecule activity is between 50 to 100%. mean any mammal, including but not limited to human 0214. As used herein “mimic' is defined as an increase in beings, including a human patient or Subject to which the the activity of a biological pathway dependent on the under compositions of the invention can be administered. The term produced biological molecule of between 10 to 100%. More mammals include human patients and non-human primates, preferably the increase of the activity of the biological path as well as experimental animals such as rabbits, rats, and way is between 25 to 100%. Even more preferably the mice, and other animals. increase of the activity the biological pathway is between 50 0210. The peptide of the present invention can be used for to 100%. the prophylaxis and/or treatment of cancer, an autoimmune disease, a fibrotic disease, an inflammatory disease, a neuro Peptides degenerative disease, an infectious disease, a lung disease, a heart and vascular disease or a metabolic disease or any other 0215. The following peptide of the invention was for disease mentioned herein in combination administration with tested for the activity as a therapeutic agent for the prophy another therapeutic compound. As used herein the term laxis and/or treatment of cancer, an infectious disease, an “combination administration of a compound, therapeutic autoimmune disease, a fibrotic disease, an inflammatory dis agent or known drug with the peptide of the present invention ease, a neurodegenerative disease, or a heart and vascular means administration of the drug and the peptide at Such time disease: US 2010/0210567 A1 Aug. 19, 2010 peptide having the amino acid sequence: TABLE 3-continued Thr-Lys-Pro-Arg-OH (Tuftsin). The following abbreviations are used for the common amino acids 0216. The term Tuftsin in brackets after the peptide referred to herein. sequence Thr-Lys-Pro-Arg-OH is an abbreviation or syn onym of said peptide. Abbreviation Amino acid 0217. Furthermore the present invention relates to the use His Histidine of the above-mentioned peptides as pharmaceutically active Ile Isoleucine Leu Leucine agents in medicine, i.e. as medicament. Advantage of the Lys Lysine peptide of the invention is that the peptide is less toxic in Met Methionine comparison to the commonly used drugs for the certain indi Phe Phenylalanine cations mentioned herein and that the peptide have less side Pro Proline Pyl Pyrrolysine effects, can be used for a long term treatment of certain Ser Serine diseases and can be easily administered. Moreover the pep Sec Selenocysteine tide are selective for certain targets and under physiological Thr Threonine conditions no toxic or noxious degradation products are Trp Tryptophan formed. Tyr Tyrosine Wall Valine 0218. As used herein, the term "peptide(s) or “peptide(s) ASX Aspartic acid or Asparagine of the invention' shall also refer to salts, deprotected form, Glx Glutamine or Glutamic acid acetylated form of the peptide, deacetylated form of the pep Xaa Any amino acid tide, enantiomers, diastereomers, racemates, prodrugs and Xle Leucine or Isoleucine hydrates of the above-mentioned peptides. Diastereomers of thea peptide are obtained when the stereochemical or chiral 0223 Some modified amino acids are indicated as fol center of one or more amino acids is changed. The enantiomer lows: has the opposite stereochemistry at all chiral centers. “D-2-Nal' is 2-naphthyl-D-alanine, 0219. The term “prodrug” refers to any precursor com “SertBu” is t-butyl serine, pound which is able to generate or to release the above “AZagly’ is aza glycine, mentioned peptide under physiological conditions. Such pro “Me' is methyl, drugs, i.e. Such precursor molecules are for instance larger Met(O) is methionine sulfoxide, peptides which are selectively cleaved in order to form one of “Pyr' and “pClu’ are pyroglutamic acid, the above-mentioned the peptides of the invention. Further “Tyr(SO3H) is sulphated tyrosine, prodrugs are protected amino acids having especially protect “Tyr(Me) is methyltyrosine, ing groups at the carboxylic acid and/or amino group. “NHEt” is ethylamide. 0220 Suitable protecting groups for amino groups are the benzyloxycarbonyl, t-butyloxycarbonyl (BOC), formyl, and EXAMPLES acetyl or acyl group. Suitable protecting groups for the car boxylic acid group are esters such as benzyl esters or t-butyl 0224. The peptides as listed above were tested for activity esterS. using the assays described in Examples 1 to 17. The tested 0221) The present invention also includes the above pep peptides are all commercially available. tides having amino acid Substitutions, deletions, additions, the Substitutions and additions including the standard DandL Example 1 amino acids and modified amino acids such as for example amidated and acetylated amino acids, wherein the therapeutic HIV-1 Experiments activity of the base peptide sequence as shown above is main 0225 CEM-SS cells were passaged in T-75 flasks prior to tained. use in the antiviral assay. On the day preceding the assay, the 0222. In the listed peptide sequences Ac' indicates an cells were split 1:2 to assure they were in an exponential acetylated residue and “NH indicates an amidated residue, growth phase at the time of infection. Total cell viability “cyclo” indicates a cyclic peptide, and “D’ indicates a D quantification was performed using a hemacytometer and optical isomer. Deacetyled amino or NH-group refers to the trypan blue exclusion. Cell viability was greater than 95% for free amino ( HH) group. the cells to be utilized in the assay. The cells were resus pended at 5x10" cells/ml in tissue culture medium and added TABLE 3 to the peptide-containing microtiter plates in a Volume of 50 microliters. The following abbreviations are used for the common amino acids referred to herein. 0226. The virus used was the lymphocytotropic strain HIV-1. Virus was obtained from NIH AIDS Research and Abbreviation Amino acid Reference Reagent Program and was grown in CEM-SS cells Ala Alanine for the production of stock virus pools. For each assay, a Arg Arginine pre-titered aliquot of virus was removed from the freezer ASn Asparagine (-80°C.) and allowed to thaw slowly to room temperature in Asp Aspartic acid (Aspartate) Cys Cysteine a biological safety cabinet. The virus was resuspended and Gln Glutamine diluted into tissue culture medium such that the amount of Glu Glutamic acid (Glutamate) virus added to each well in a volume of 50 microliters was the Gly Glycine amount determined to give between 85% to 95% cell killing after 6 days post-infection. TCIDso calculations by endpoint US 2010/0210567 A1 Aug. 19, 2010 34 titration in CEM-SS cells indicated that the multiplicity of 0231. Antiviral activity infection was approximately 0.01. AZT (nucleoside reverse 0232 Compound Cytotoxicity transcriptase inhibitor; NRTI) and indinavir (protease inhibi HepG2-2.2.15 cells were plated in 96-well microtiter plates. tor; PI) were used as positive control antiviral compounds. After 16-24 hours the confluent monolayer of HepG2-2.2.15 cells was washed and the medium was replaced with com Plate Format plete medium containing test peptide-10 micrograms per ml in duplicate. Lamivudine (3TC) was used as the positive 0227 Each plate contained cell control wells (cells only), control, while media alone was added to the cells as a negative virus control wells (cells plus virus), drug cytotoxicity wells control (virus control). Three days later the culture medium (cells plus peptide only), peptide colorimetric control wells was replaced with fresh medium containing the peptide. Six (peptide only) as well as experimental wells (peptide—10 days following the initial administration of the peptide, the micrograms per ml plus cells plus virus). Samples were cell culture Supernatants was collected, treated with pronase evaluated for antiviral efficacy with triplicate measurements and DNAse and then used in a real-time quantitative TaqMan and with duplicate measurements to determine cellular cyto PCR assay. The PCR-amplified HBV DNA was detected in toxicity, if detectable. real-time by monitoring increases in fluorescence signals that 0228. At assay termination, the plates were stained with result from the exonucleolytic degradation of a quenched the soluble tetrazolium-based dye MTS (CelTiter 96 fluorescence probe molecule that hybridizes to the amplified Reagent, Promega) to determine cell viability and quantify HBV DNA. For each PCR amplification, a standard curve peptide toxicity. MTS is metabolized by the mitochondrial was simultaneously generated using dilutions of purified enzymes of metabolically active cells to yield a soluble for HBV DNA. Antiviral activity was calculated from the reduc mazan product, allowing the rapid quantitative analysis of tion in HBV DNA levels (% virus control). A novel dye cell viability and peptide cytotoxicity. This reagent is a stable, uptake assay was then employed to measure cell viability, single solution that does not require preparation before use. which is used to calculate toxicity (% cell control). At assay termination, 20-25 microliters of MTS reagent was Results from HBV Experiments: added per well and the microtiter plates were then incubated for 5 hours at 37° C., and 5% CO to assess cell viability. Adhesive plate sealers were used in place of lids, the sealed plates were inverted several times to mix the soluble forma % inhibition of Zan product and the plate was read spectrophotometrically at HBV replication in % Cell 490/560 nm with a Molecular Devices Vmax plate reader. Compound HEP G2 cells Viability 0229. The overall assay performance was valid based Tuftsin 41.2 100 upon judgement of the positive control compounds AZT and 3TC 92.0 95.8 indinavir exhibiting the expected levels of antiviral activity. (positive control) Macroscopic observation of the cells in each well of the microtiter plate confirmed the cytotoxicity results obtained following staining of the cells with the MTS metabolic dye. Example 3 Results from HIV Experiments: HCMV Experimental Assay System 0233 MRC-5 cells (human embryonal lung fibroblasts) were obtained from the American Type Culture Collection % CPE reduction in (ATCC CCL-171; Rockville, Md.) and grown in Eagle's HIV-1 infected % Cell Minimum Essential Medium with Earle's BSS (EMEM) Compound CEM-SS cells viability supplemented with 10% fetal bovine serum (FBS), 0.1 mM Tuftsin O.O 1OO non-essential amino acids, 1.0 mMSodium pyruvate, 2.0 mM AZT 99 97 L-Glutamine, 100 units/ml Pencillin and 100 micrograms/ml (positive control) Streptomycin. Cells were split twice a week 1:2. Indinavir 1OO 93 0234 HCMV strain AD 169 was obtained from ATCC (positive control) (ATCC VR-538). Virus stocks were prepared by infecting 80% confluent MRC-5 cells at a minimal multiplicity of infection in MRC-5 growth medium containing 2% FBS. Example 2 Monolayers were incubated at 37° C., 5% CO, until 90%- 95% viral cytopathic effect (CPE) was observed (10-13 days). HBV Experimental Assay System Culture medium was then collected from the cells, centri fuged at low speed to remove cellular debris, aliquoted in 1 ml 0230 HepG2-2.2.15 is a stable cell line containing the Volumes and stored at -80° C. as stock virus. hepatitis B virus (HBV) ayw strain genome (ATCC Cat. No. 0235 MRC-5 cells were seeded at 75,000 cells/well in 24 CRL-1 1997). Antiviral compounds blocking any late step of well plates using MRC-5 growth medium. The plates were viral replication Such as transcription, translation, pregenome incubated overnight at 37° C., 5% CO. The following day, encapsidation, reverse transcription, particle assembly and media was removed and 100 plaque forming units (pfu) of release can be identified and characterized using this cell line. HCMV was added to the wells. Virus was allowed to adsorb In this assay, an active compound will reduce the production onto the cells for 1 hour at 37° C., 5% CO. Peptide was of secreted HBV from cells, measured by utilizing real time diluted—10 micrograms per ml in assay medium contain quantitative PCR (TaqMan) assay to directly and accurately ing 0.5% Methylcellulose. After the incubation period, 1 ml measure HBV DNA copies. The analysis of this data allows to of each peptide solution was added to the wells without aspi calculate: rating the virus inoculums. The plates were incubated for US 2010/0210567 A1 Aug. 19, 2010 35

7-10 days to allow for plaque formation. Ganciclovir was Example 5 used as positive control. Cultures were examined microscopi cally and toxicities were noted. The media was the aspirated Pseudomonas aeruginosa Assay from the wells and the cells were fixed and stained using 20% methanol containing Crystal Violet followed by enumeration 0239. The antibacterial assay was conducted using clear, of plaques by microscopic inspection. U-bottom 96-well microtiter plates. Cation-adjusted Muel 0236. For cytotxicity testing, MRC-5 cells were seeded at ler-Hinton Broth (MHB) was used for testing Pseudomonas 2,500 cells/well in 96 well plates using growth medium. The aeruginosa. The peptide of the invention (0.1 ml of each—10 plates were incubated overnight at 37° C., 5% CO. The micrograms per ml ) was dispensed into wells in duplicate. following day, peptide was added and tested in duplicates. Then the wells were inoculated with 5x10 CFU/mL After a 6 days incubation period, cell viability was measured Pseudomonas aeruginosa in 0.1 ml Volume. For control pur using CellTiter96 Solution (Promega). Plates were incubated poses, each plate included 4 wells containing media without for additional 4 hours at 37°C. Adhesive plate sealers were used in place of lids, the sealed plates were inverted several bacterial inoculum and 4 wells containing medium with times to mix the soluble formazan product and the plate was inoculum but without peptide. The plates were incubated for read spectrophotometrically at 490/560 nm with a Molecular 12 hat 37°C., and read visually 18-24 hours post-incubation. Devices Vmax plate reader. Growth control of Pseudomonas aeruginosa was examined 0237. The overall assay performance was valid based first to determine adequacy of media preparations and growth upon judgement of the positive control compound Ganciclo conditions. Acceptable growth is defined as 22 mm wide vir exhibiting the expected levels of antiviral activity. Mac button of cells at the bottom of each sample well, or obvious roscopic observation of the cells in each well of the microtiter turbidity in the culture supernatant. Test wells were examined plate confirmed the cytotoxicity results obtained following and scored as positive/negative for activity. A positive score staining of the cells with the MTS metabolic dye. for activity is based on complete inhibition of macroscopic Results from HCMV Assay: growth of the test Pseudomonas aeruginosa. Results from Pseudomonas aeruginosa Assay:

% plaque % Cell Compound reduction viability Compound % inhibition

Tuftsin O.O 1OO Tuftsin O.O Ganciclovir 1OO 1OO (positive control) Example 6 Example 4 Streptococcus pneumoniae Assay Methicillin Resistant Staphylococcus Aureus (MRSA) Assay 0240. The antibacterial assay was conducted using clear, 0238. The antibacterial assay was conducted using clear, U-bottom 96-well microtiter plates. Cation-adjusted Muel U-bottom 96-well microtiter plates. Cation-adjusted Muel ler-Hinton Broth (MHB) was used for testing Streptococcus ler-Hinton Broth (MHB) was used for testing MRSA. The pneumoniae. The peptide of the invention (0.1 ml of each— peptide of the invention (0.1 ml of each—10 micrograms per 10 micrograms per ml ) was dispensed into wells in dupli ml ) was dispensed into wells in duplicate. Then the wells cate. Then the wells were inoculated with 5x10 CFU/mL were inoculated with 5x10 CFU/mL MRSA in 0.1 ml vol Streptococcus pneumoniae in 0.1 ml Volume. For control ume. For control purposes, each plate included 4 wells con purposes, each plate included 4 wells containing media with taining media without bacterial inoculum and 4 wells con out bacterial inoculum and 4 wells containing medium with taining medium with inoculum but without peptide. The inoculum but without peptide. The plates were incubated for plates were incubated for 12 h at 37° C., and read visually 12 hat 37°C., and read visually 18-24 hours post-incubation. 18-24 hours post-incubation. Growth control of MRSA was Growth control of Streptococcus pneumoniae was examined examined first to determine adequacy of media preparations first to determine adequacy of media preparations and growth and growth conditions. Acceptable growth is defined as 22 conditions. Acceptable growth is defined as 22 mm wide mm wide button of cells at the bottom of each sample well, or button of cells at the bottom of each sample well, or obvious obvious turbidity in the culture supernatant. Test wells were turbidity in the culture supernatant. Test wells were examined examined and scored as positive/negative for activity. A posi and scored as positive/negative for activity. A positive score tive score for activity is based on complete inhibition of for activity is based on complete inhibition of macroscopic macroscopic growth of the test MRSA. growth of the test Streptococcus pneumoniae. Results from MRSA Assay: Results from Streptococcus pneumoniae Assay:

Compound % inhibition Compound % inhibition Tuftsin O.O Tuftsin O.O US 2010/0210567 A1 Aug. 19, 2010 36

Example 7 tion. The ensuing S phase starts when DNA synthesis com mences; when it is complete, all of the chromosomes have Mycobacterium tuberculosis Assay been replicated. The cell then enters the G phase, which lasts 0241 The antibacterial assay was conducted using clear, until the cell enters mitosis. Significant protein synthesis U-bottom 96-well microtiter plates. Middlebrook 7H12 assay occurs during this phase, mainly involving the production of medium was used for testing drug-resistant Mycobacterium microtubules, which are required during the process of mito tuberculosis. The peptide of the invention (0.1 ml of each— sis. Inhibition of protein synthesis during G2 phase prevents 10 micrograms per ml ) was dispensed into wells in dupli the cell from undergoing mitosis. cate. Then the wells were inoculated with 5x10 CFU/mL 0245 Disregulation of the cell cycle components may lead Mycobacterium tuberculosis in 0.1 ml volume. For control to tumor formation. purposes, each plate included 4 wells containing media with 0246 Propidium iodide is an intercalating agent and a out bacterial inoculum and 4 wells containing medium with fluorescent molecule that can be used to stain DNA. Cells inoculum but without peptide. The plates were incubated for were incubated for 24 hours with test peptide—10 micro seven days at 37° C., and read visually thereafter. Growth grams per ml or left untreated. After that cells were control of Mycobacterium tuberculosis was examined first to trypsinized, suspended in medium+10% FCS, centrifuged determine adequacy of media preparations and growth con (1000 rpm, 5min), and the cell pellet resuspended in PBS (1 ditions. Acceptable growth is defined as 22 mm wide button ml). The cells were pipetted into 2.5 ml absolute EtOH (final of cells at the bottom of each sample well, or obvious turbidity concentration approx. 70%) and incubated on ice for 15 min. in the culture Supernatant. Test wells were examined and Thereafter, cells were pelleted at 1500 rpm for 5 min and scored as positive/negative for activity. A positive score for resuspended in Propidium iodide solution in PBS. After incu activity is based on complete inhibition of macroscopic bation for 40 min at 37°C., cells were analyzed in the FACS. growth of the test Mycobacterium tuberculosis. The drug Results from Cell Cycle Assay: resistant Mycobacterium tuberculosis that was used in the assay is resistant against following medicaments: para-ami nosalicylic acid (PAS), streptomycin and isoniazid (INH). Results from Mycobacterium tuberculosis Assay: Cell cycle analysis Compound GOG1 S G2FM Tuftsin 55.1 32.6 13.3 Compound % inhibition Tuftsin O.O Example 9 T Cell Proliferation Assay Example 8 0247 Human Peripheral Blood Mononuclear Cells Cell Cycle Assay (PBMC) were obtained from normal human donors. The T 0242 Human A549 cells (carcinomic human alveolar cell proliferation was induced by stimulation of the cells with basal epithelial cells) were utilized in the experiments the T cell mitogen phytohemagglutinin (PHA), either in the employing the Propidium iodide cell cycle assay. The eukary absence (positive proliferation control), or in the presence of otic cell cycle is a series of events that take place in a cell test peptide-10 micrograms per ml to examine their leading to its replication. effects on the T cell proliferating response. 10/well PBMC 0243 The regulation of the cell cycle involves steps cru were plated in 96-well microtiter plates and assayed in dupli cial to the cell, including detecting and repairing genetic cate with the peptide. Cell cultures were incubated at 37°C. damage, and provision of various checks to prevent uncon for 3 days in a 5% CO incubator and were thereafter pulsed trolled cell division. The molecular events that control the cell with 1 microCi/well H-thymidine for additional 12 hours of cycle are ordered and directional; that is, each process occurs culture. At the end of incubation time, the plates were har in a sequential fashion. vested and the cells counted by liquid scintillation for the 0244. The cell cycle consists of four distinct phases: G incorporation of H-thymidine as a measure of T cell prolif phase, S phase, G2 phase (collectively known as interphase) eration. and M phase. M phase is itself composed of two tightly Results from T Cell Proliferation Assay: coupled processes: mitosis, in which the cell's chromosomes are divided between the two daughter cells, and cytokinesis, in which the cell's cytoplasm divides forming distinct cells. % of PHA induced Activation of each phase is dependent on the proper progres Compound control sion and completion of the previous one. Cells that have temporarily or reversibly stopped dividing are said to have Tuftsin 91.9 entered a state of quiescence called Go phase. The relatively brief Mphase consists of nuclear division and cytoplasmic division. The first phase within interphase, from the end of the Example 10 previous M. phase till the beginning of DNA synthesis is called G (G indicating gap or growth). During this phase the B Cell Proliferation Assay biosynthetic activities of the cell resume at a high rate. This 0248 Human Peripheral Blood Mononuclear Cells phase is marked by Synthesis of various enzymes that are (PBMC) were obtained from normal human donors. The B required in S phase, mainly those needed for DNA replica cell proliferation was induced by stimulation of the cells with US 2010/0210567 A1 Aug. 19, 2010 37 the B cell mitogen Staphylococcus aureus Cowans I (SAC) Results from Apoptosis Induction Assay: plus Interleukin-2, either in the absence (positive prolifera tion control), or in the presence of test peptide-10 micro grams per ml to examine their effects on the B cell response. 10/well PBMC were plated in 96-well microtiter plates and Compound % of induction assayed in duplicate with the peptide. Cell cultures were Tuftsin 18.6 incubated at 37°C. for 3 days in a 5% CO incubator and were thereafter pulsed with 1 microCi/well H-thymidine for addi tional 12 hours of culture. At the end of incubation time, the plates were harvested and the cells counted by liquid scintil Example 13 lation for the incorporation of H-thymidine as a measure of B cell proliferation. Apoptosis Prevention Assay Results from B Cell Proliferation Assay: 0251 Human A549 cells (carcinomic human alveolar basal epithelial cells) were utilized in the experiments employing the Annexin-5 apoptosis assay. Annexin-5 is a % of SACIL2 member of a highly conserved protein family that binds acidic induced phospholipids in a calcium-dependent manner. Annexin-5 Compound control possesses a high affinity for phosphatidylserine. Phosphati dylserine is translocated from the inner side of the plasma Tuftsin 103.6 membrane to the outer layer when cells undergo death by apoptosis or cell necrosis and serves as a signal by which cell destined for death are recognized by phagocytes. A549 cells Example 11 were pretreated for 30 min with test peptide—10 micrograms Phagocytosis Assay per ml followed by the exposure to C2 ceramide. Ceramide mediates cell apoptosis through the activation of the mitogen 0249 RAW264.7 (Mouse leukaemic monocyte macroph activating protein kinase (MAPK) and the stress activated age cell line) cells were obtained from ATCC and grown in kinase (JNK/SAPK). C2 ceramide is a synthetic, membrane RPMI 1640 medium containing 10% FBS. Cells were incu soluble analog of ceramide. bated in 12x75 mm tubes at 37° C. with test peptide-10 Results from Apoptosis Prevention Assay: micrograms per ml for 30 min prior to adding Fluorescein labeled Escherichia coli bacteria as the agent to be ingested. After the cells were incubated for additional 60 min at 37° C. and allowed to ingest the Fluorescein-labeled Escherichia % prevention of coli bacteria, cells were fixed with 1% paraformaldehyde. ceramide induced The samples were then analyzed by flow cytometry to deter Compound apoptosis mine the amount of phagocytosis as a function of brightness Tuftsin O.O (the greater the phagocytic activity, the more fluorescence in the macrophage population). Data are reported as % positive and the mean fluorescence intensity (MFI) of positively stained cells. Example 14 Results from Phagocytosis Assay: Th1/Th2 Cytokine Profiling Assay 0252. The Balb/c mice (originated in 1923, it is a popular % of control strain and is used in many different research disciplines. Also Compound phagocytosis classified as an inbred from the production of 20 or more Successive brother-sister matings, the Balb/c mouse is albino Tuftsin 102.9 and small in size) were immunized on Days 1, 15, and 29 with Ovalbumin (Ovalbumin is the main protein found in egg white, commonly used to stimulate an immunological reac Example 12 tion in test animals) in PBS (5 micrograms/injection). On day 50, spleens of the mice were harvested (3 weeks after last Apoptosis Induction Assay boost with Ovalbumin). Cells were cultured (2x10/well in 0250) Human A549 cells (carcinomic human alveolar triplicate) and incubated with culture medium or test pep basal epithelial cells) were utilized in the experiments tide—10 micrograms per ml for 30 min. Thereafter, addi employing the Annexin-5 apoptosis assay. Annexin-5 is a tional Ovalbumin was added to the cells at 10 micrograms/ml member of a highly conserved protein family that binds acidic for in vitro restimulation of the cells. 72 hours later, cell phospholipids in a calcium-dependent manner. Annexin-5 Supernatants were harvested and assayed using the Becton possesses a high affinity for phosphatidylserine. Phosphati Dickinson Mouse Th1/Th2 Cytokine CBA Kit. This kit can dylserine is translocated from the inner side of the plasma be used to measure Interleukin-2 (IL-2), Interleukin-4 (IL-4), membrane to the outer layer when cells undergo death by Interleukin-5 (IL-5), Interferon-Y (IFN-Y), and Tumor Necro apoptosis or cell necrosis and serves as a signal by which cell sis Factor-O. (TNF-C.) protein levels in a single sample. The kit destined for death are recognized by phagocytes. Test pep performance has been optimized for analysis of physiologi tide-micrograms per ml were exposed for 24 hours to the cally relevant concentrations (pg/ml levels) of specific cytok A549 cells before they were analyzed for signs of apoptosis. ine proteins in tissue culture Supernatants and serum samples. US 2010/0210567 A1 Aug. 19, 2010

Results from Th1/Th2 Cytokine Assay:

TNF-a spleen IFNY spleen IL-4 spleen IL-5 spleen cells: TH1 cells: TH1 IL-2 spleen cells: TH2 cells: TH2 response (% of response (% of cells (% of response (% response (% of Compound control) control) control) of control) control) Tuftsin 127.5 63.1 112.1 103.5 107.6

Example 15 Results from Endothelial Cell Migration Assay: TNF Alpha Production Assay % inhibition of 0253) Human Peripheral Blood Mononuclear Cells Compound migration (PBMC) were obtained from normal human donors. The macrophages were prepared by adherence of PBMC to the Tuftsin 35 plastic wells of the plates. After 8 days in culture in the presence of recombinant human macrophage-colony Stimu lating factor at 2 ng/ml, differentiated macrophages were Example 17 preincubated with test peptide-10 micrograms per ml for 30 min, followed by in-well stimulation by the addition of Endothelial Tube Formation Assay lipopolysaccharide at a final concentration of 200 ng/ml. Not 0256 The endothelial tube formation assay is based on the stimulated macrophages served as negative background con ability of endothelial cells to form three-dimensional capil trol. lary-like tubular structures when cultured on a gel of base 0254. After overnight incubation, supernatants from the ment membrane extract. The endothelial tube formation control and LPS-stimulated cultures were harvested and assay represents a powerful model for studying inhibition and assayed for TNF alpha production employing a TNF alpha induction of angiogenesis. Pre-labeled HUVEC with Calcein specific ELISA. AM were seeded in a 96-well culture plate coated with extra cellular metrix (Chemicon international Cat. ECM625) and Results from TNF Alpha Assay: treated with test peptide-10 micrograms per ml in full growth medium. Positive control was vehicle only. The endothelial cells were allowed to form tubes foe 20 hours and Compound % of LPS induction were then examined under an inverted fluorescent micro Scope. Duplicate wells for each treatment were photographed Tuftsin 119.8 and quantitatively analyzed for an average tubule length using image analysis software ImageProPlus. Raw data were expressed as average tubule lengths in pixelsistandard devia Example 16 tion. Statistic p values were computed using the Student's t-teSt. Endothelial Cell Migration Assay Results from Endothelial Tube Formation Assay: 0255 Endothelial cell migration is a prerequisite for the process of neo-vascularization orangiogenesis which is cru % inhibition of tube cial for on-site recruitment of blood vessel formation. Pri Compound formation mary Human endothelial cells (HUVEC) were seeded in Tuftsin 18 insert chambers with 3 micrometer pore size of multi-tran swell plate for 6 hours at 37° C. in Endothelial Cell Basal Medium (EBM) supplemented with 0.1% bovine serum albu min. Thereafter, designated concentration of test peptide-10 Example 18 micrograms per ml was added in duplicate wells. The Mother Milk Formulation endothelia were allowed to migrate for 22 hours at 37° C. then, migrated cells were fixed and stained with Hoechst 0257 Methods to prepare mother milk or artificial mother 33342 dye. Images of 3 fields per insert were taken and the milk formulations or mother milk substitutes are described in number of migrated cells per field were quantified using the WO03043429, U.S. Pat. No. 5,962,062, WO0030461, ImageProPlus software. Data were analyzed for the average EP0527283, EP0832565 number of the migrated cells and standard deviation of six 0258. One example of an artificial mother milk or mother data points for each treatment condition. Active test peptide milk substitute formulation is provided in the following while against HUVEC migration was determined based on 50% also the other formulations disclosed in the above mentioned inhibition of migrated cells as compared with the control. references can be used and are included herewith by refer Statistic p values were computed using the Student's t-test. CCC. US 2010/0210567 A1 Aug. 19, 2010 39

0259. The milk substitute contains, by weight, approxi are stirred and heated at 50° C., until a clear solution has been mately 15% skimmed milk solids, approximately 75% dem formed. Then the composition is cooled to room temperature ineralized water, approximately 9%. Soya oil, approximately under stirring. The lotion contains 5% of peptide 1 for medi 0.02% of carrageenates, 0.2% lecithin, and approximately cal use. Optionally peptide 2 could be added in an amount 0.2% of disodium hydrogenphosphate. form 0.01 to 0.5g.

SEQUENCE LISTING

<16 Os NUMBER OF SEO ID NOS : 1

<21 Os SEQ ID NO 1 &211s LENGTH: 4 212s. TYPE: PRT <213> ORGANISM: Homo sapiens <4 OOs SEQUENCE: 1 Thr Lys Pro Arg 1.

0260. In a first step, the solubilizing aqueous medium is 1-12. (canceled) produced, comprises, by weight, approximately 75% of 13. A pharmaceutical composition comprising a peptide water, approximately 0.02% of carrageenate and approxi consisting of the sequence Thr-Lys-Pro-Arg-OH (SEQ ID mately 0.2% of disodium hydrogenphosphate. NO:1). 0261 The skimmed milk powder is then added to the 14. The pharmaceutical composition of claim 13, wherein solution for 10 min at 60° C. and dissolved in the liquid. said composition is incorporated in a nutritional formulation. 0262 Then soya oil and lecithin are added to the milk 15. The pharmaceutical composition of claim 14, wherein substitute composition at 60° C. The milk composition is the nutritional formulation is an artificial mother milk formu allowed to stand 30 min at 55° C. After pasteurization, the lation or mother milk substitute suitable for oral administra peptide of the invention is added in liquid or powder form in tion to newborns, toddlers and infants. Such a quantity that the milk composition obtained comprises 16. The pharmaceutical composition of claim 13, wherein an amount of 5-50 micrograms, preferably 10-40 micrograms said composition is prepared as a lyophilized formulation or per 100 ml of milk composition. Optionally peptide 2 could a buffered liquid formulation. be added in similar or Smaller amounts to the obtained com 17. The pharmaceutical composition of claim 13, wherein position. said composition comprises at least one pharmaceutically acceptable carrier, cryoprotectant, lyoprotectant, excipient or Example 19 diluent. 18. A method of treatment of cancer, autoimmune disease, Gel Formulation fibrotic disease, inflammatory disease, neurodegenerative disease, infectious disease, lung disease, heart and vascular 0263 0.5g of peptide disease and metabolic disease, the method comprising, 1.6 g of isopropanol administering to a patient in need thereof, a therapeutically 1.0 g of glycerol effective amount of 1.6 g of polyoxyethylene-polyoxypropylene copolymer a pharmaceutical composition comprising a peptide con 12500 (Pluronic F127) sisting of the sequence Thr-Lys-Pro-Arg-OH (SEQ ID 5.3. g of water NO: 1) or salts or hydrates thereof, wherein administra are mixed for 10 minutes and then heated to 85°C. under tion of the pharmaceutical composition treats said dis continuous stirring for 15 minutes. The Solution is cooled to CaSCS. room temperature under stirring. During the cooling phase 19. The method of claim 18, wherein the cancer, autoim the solution begins to gel at a temperature of about 45° C. to mune disease, fibrotic disease, inflammatory disease, neuro form a clear gel. The gel contains 5% of the peptide 1 for degenerative disease, infectious disease, lung disease, heart medical use. Optionally peptide 2 could be added in an and vascular disease or metabolic disease is selected from amount form 0.01 to 0.5g. Hepatitis B Virus infection, diseases caused by Hepatitis B Virus infection, acute hepatitis, chronic hepatitis, fulminant Example 20 liver failure, liver cirrhosis and cancer associated with Hepa titis B Virus infection. Lotion Formulation 20. The method of claim 18, wherein the peptide is admin istered by intravenous administration, oral administration, or 0264 0.5g of peptide administration by inhalation. 1.9 g of isopropanol 21. The method of claim 18, wherein the peptide is admin 1.0 g of dimethylisosorbide istered as a lyophilized formulation or as a buffered liquid 1.0 g of polyoxyethylene-polyoxypropylene copolymer formulation 12500 (Pluronic F127) 5.6 g of water