Proteins for the treatment of epithelial barrier function disorders

Abstract

The disclosure relates to therapeutic proteins and pharmaceutical compositions comprising said proteins, which have utility in treating various human diseases. In particular aspects, the disclosed therapeutic proteins are useful for treating human gastrointestinal inflammatory diseases and gastrointestinal conditions associated with decreased epithelial cell barrier function or integrity. Further, the disclosed therapeutic proteins are useful for treating human inflammatory bowel disease, including inter alia, Crohn's disease and ulcerative colitis.

1 . A method of treating a gastrointestinal epithelial cell barrier function disorder, comprising:
 a. administering to a patient in need thereof a pharmaceutical composition, comprising:
 i. a therapeutic protein comprising an amino acid sequence having at least about 85% sequence identity to SEQ ID NO: 3 and/or SEQ ID NO: 5; and 
 ii. a pharmaceutically acceptable carrier. 
   
     
     
         2 . The method of  claim 1 , wherein the gastrointestinal epithelial cell barrier function disorder is a disease associated with decreased intestinal epithelium integrity. 
     
     
         3 . The method of  claim 1 , wherein the gastrointestinal epithelial cell barrier function disorder is at least one selected from the group consisting of: inflammatory bowel disease, Crohn's disease, ulcerative colitis, pouchitis, irritable bowel syndrome, enteric infections,  Clostridium difficile  infections, metabolic diseases, obesity, type 2 diabetes, non-alcoholic steatohepatitis, non-alcoholic fatty liver disease, liver disorders, alcoholic steatohepatitis, celiac disease, necrotizing enterocolitis, gastro intestinal disorders, short bowel syndrome, GI mucositis, chemotherapy induced mucositis, radiation induced mucositis, oral mucositis, interstitial cystitis, neurological disorders, cognitive disorders, Alzheimer's, Parkinson's, multiple sclerosis, autism, chemotherapy associated steatohepatitis (CASH), and pediatric versions of the aforementioned diseases. 
     
     
         4 . The method of  claim 1 , wherein the gastrointestinal epithelial cell barrier function disorder is inflammatory bowel disease. 
     
     
         5 . The method of  claim 1 , wherein the gastrointestinal epithelial cell barrier function disorder is Crohn's disease. 
     
     
         6 . The method of  claim 1 , wherein the gastrointestinal epithelial cell barrier function disorder is ulcerative colitis. 
     
     
         7 . The method of  claim 1 , wherein the therapeutic protein comprises an amino acid sequence having at least about 90% sequence identity to SEQ ID NO: 3 and/or SEQ ID NO: 5. 
     
     
         8 . The method of  claim 1 , wherein the therapeutic protein comprises an amino acid sequence having at least about 95% sequence identity to SEQ ID NO: 3 and/or SEQ ID NO: 5. 
     
     
         9 .- 12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein the therapeutic protein comprises the amino acid sequence of SEQ ID NO: 3. 
     
     
         14 . The method of  claim 1 , wherein the therapeutic protein comprises the amino acid sequence of SEQ ID NO: 5. 
     
     
         15 . The method of  claim 1 , wherein administering comprises rectal, parenteral, intravenous, topical, oral, dermal, transdermal, or subcutaneous administration. 
     
     
         16 . The method of  claim 1 , wherein administering is to the: mouth, gastrointestinal lumen, and/or intestines of the patient. 
     
     
         17 . The method of  claim 1 , wherein the patient experiences a reduction in at least one symptom associated with the gastrointestinal epithelial cell barrier function disorder. 
     
     
         18 . The method of  claim 1 , wherein the patient experiences a reduction in at least one symptom associated with the gastrointestinal epithelial cell barrier function disorder selected from the group consisting of: abdominal pain, blood in stool, pus in stool, fever, weight loss, frequent diarrhea, fatigue, reduced appetite, tenesmus, and rectal bleeding. 
     
     
         19 . The method of  claim 1 , wherein administering reduces one or more of: gastrointestinal inflammation in the patient and intestinal mucosal inflammation in the patient. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 1 , wherein administering increases one or more of the production of mucin in intestinal tissue in the patient, intestinal epithelium wound healing in the patient, and intestinal epithelial cell proliferation in the patient. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . The method of  claim 1 , further comprising: administering at least one second therapeutic agent to the patient. 
     
     
         25 . The method of  claim 1 , further comprising: administering at least one second therapeutic agent to the patient, said second therapeutic agent selected from the group consisting of: an anti-diarrheal, a 5-aminosalicylic acid compound, an anti-inflammatory agent, an antibiotic, an antibody, an anti-cytokine agent, an anti-inflammatory cytokine agent, a steroid, a corticosteroid, and an immunosuppressant. 
     
     
         26 . A pharmaceutical composition, comprising:
 a. a therapeutic protein comprising an amino acid sequence having at least about 85% sequence identity to SEQ ID NO: 3 and/or SEQ ID NO: 5; and   b. a pharmaceutically acceptable carrier.   
     
     
         27 .- 36 . (canceled) 
     
     
         37 . An expression vector, comprising: a polynucleotide, which encodes a protein comprising an amino acid sequence having at least about 85% sequence identity to SEQ ID NO: 3 and/or SEQ ID NO: 5. 
     
     
         38 .- 45 . (canceled) 
     
     
         46 . A host cell, comprising: an exogenous polynucleotide, which encodes a protein comprising an amino acid sequence having at least about 85% sequence identity to SEQ ID NO: 3 and/or SEQ ID NO: 5. 
     
     
         47 .- 60 . (canceled) 
     
     
         61 . A method of producing a protein, comprising: culturing the host cell of  claim 46 , under conditions sufficient for expression of the encoded protein. 
     
     
         62 . An isolated therapeutic protein, comprising: an amino acid sequence having at least about 85% sequence identity to SEQ ID NO: 3 and/or SEQ ID NO: 5. 
     
     
         63 .- 74 . (canceled)