Proteins for the treatment of epithelial barrier function disorders
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 increasing epithelial barrier integrity in the gut of a patient, the method comprising:
administering to a patient in need thereof a pharmaceutical composition, comprising:
i) a therapeutic protein comprising the amino acid sequence of SEQ ID NO: 3, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, or SEQ ID NO: 19; and
ii) a pharmaceutically acceptable carrier,
wherein the patient has a disorder selected from the group consisting of: inflammatory bowel disease, pouchitis, irritable bowel syndrome, celiac disease, necrotizing enterocolitis, short bowel syndrome, GI mucositis, chemotherapy-induced mucositis, radiation-induced mucositis, oral mucositis, and pediatric versions of the aforementioned diseases.
2. The method of claim 1 , wherein the disorder is inflammatory bowel disease.
3. The method of claim 1 , wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
4. The method of claim 1 , wherein the patient is a pediatric patient.
5. The method of claim 1 , wherein the therapeutic protein increases electrical resistance in an in vitro transepithelial electrical resistance (TEER) assay.
6. A method of treating a disorder, the method comprising administering to a patient in need thereof a pharmaceutical composition, wherein the pharmaceutical composition comprises:
i) a therapeutic protein comprising the amino acid sequence of SEQ ID NO: 7 with 0, 1, 2, 3, 4, or 5 substitutions in the amino acid sequence, wherein the substitutions are at amino acids 53, 83, 84, 147, and/or 151 of SEQ ID NO: 7, and
ii) a pharmaceutically acceptable carrier; and
wherein the disorder is selected from the group consisting of: inflammatory bowel disease, pouchitis, irritable bowel syndrome, celiac disease, necrotizing enterocolitis, short bowel syndrome, GI mucositis, chemotherapy-induced mucositis, radiation-induced mucositis, oral mucositis, and pediatric versions of the aforementioned diseases.
7. The method of claim 6 , wherein the therapeutic protein comprises the amino acid sequence of SEQ ID NO: 3, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17, or SEQ ID NO: 19.
8. The method of claim 6 , wherein the amino acid at position 147 is valine, the amino acid at position 151 is serine, the amino acid at position 84 is aspartic acid, the amino acid at position 83 is serine, or the amino acid at position 53 is serine.
9. The method of claim 6 , wherein the amino acid at position 147 is valine, and the amino acid at position 151 is serine.
10. The method of claim 6 , wherein the amino acid at position 84 is aspartic acid, and the amino acid at position 147 is valine, and the amino acid at position 151 is serine.
11. The method of claim 6 , wherein the amino acid at position 83 is serine, and the amino acid at position 147 is valine, and the amino acid at position 151 is serine.
12. The method of claim 6 , wherein the amino acid at position 53 is serine, and the amino acid at position 84 is aspartic acid, and the amino acid at position 147 is valine, and the amino acid at position 151 is serine.
13. The method of claim 6 , wherein the amino acid at position 53 is serine, the amino acid at position 83 is serine, the amino acid at position 147 is valine, and the amino acid at position 151 is serine.
14. The method of claim 6 , wherein the amino acid at position 147 is not cysteine, the amino acid at position 151 is not cysteine, the amino acid at position 83 is not asparagine, and/or the amino acid at position 53 is not asparagine.
15. The method of claim 6 , wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.
16. The method of claim 6 , wherein the therapeutic protein increases electrical resistance in an in vitro transepithelial electrical resistance (TEER) assay.