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 treating a disorder, the method comprising:
administering to a patient in need thereof a pharmaceutical composition comprising:
i. a therapeutic protein comprising an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 19; and
ii. a pharmaceutically acceptable carrier,
wherein the disorder is at least one selected from the group consisting of: inflammatory bowel disease, Crohn's disease, ulcerative colitis, pouchitis, irritable bowel syndrome, Clostridium difficile infections, 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 therapeutic protein comprises an amino acid sequence having at least about 97% sequence identity to SEQ ID NO: 19.
3. The method of claim 1 , wherein the therapeutic protein comprises an amino acid sequence having at least about 98% sequence identity to SEQ ID NO: 19.
4. The method of claim 1 , wherein the therapeutic protein comprises an amino acid sequence having at least about 99% sequence identity to SEQ ID NO: 19.
5. The method of claim 1 , wherein the therapeutic protein comprises the amino acid sequence of SEQ ID NO: 19.
6. The method of claim 1 , wherein administering comprises rectal, parenteral, intravenous, topical, oral, dermal, transdermal, or subcutaneous administration.
7. The method of claim 1 , wherein administering is to the: mouth, gastrointestinal lumen, and/or intestines of the patient.
8. The method of claim 1 , wherein the patient experiences a reduction in at least one symptom associated with the disorder.
9. The method of claim 1 , wherein the patient experiences a reduction in at least one symptom associated with the 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.
10. The method of claim 1 , wherein treating comprises one or more of: reducing gastrointestinal inflammation in the patient, reducing intestinal mucosal inflammation in the patient, increasing the production of mucin in intestinal tissue in the patient, increasing intestinal epithelium wound healing in the patient, and increasing intestinal epithelial cell proliferation in the patient.
11. The method of claim 1 , further comprising: administering at least one second therapeutic agent to the patient.
12. The method of claim 1 , wherein the therapeutic protein comprises the amino acid sequence of SEQ ID NO: 19 with a mutation of the amino acid at position 147 to valine.
13. The method of claim 1 , wherein the therapeutic protein comprises the amino acid sequence of SEQ ID NO: 19 with a mutation of the amino acid at position 151 to serine.
14. The method of claim 1 , wherein the therapeutic protein comprises the amino acid sequence of SEQ ID NO: 19 with a mutation of the amino acid at position 147 to valine, and a mutation of the amino acid at position 151 to serine.
15. The method of claim 1 , wherein the therapeutic protein comprises the amino acid sequence of SEQ ID NO: 19 with a mutation of the amino acid at position 84 to aspartic acid.
16. The method of claim 1 , wherein the therapeutic protein comprises the amino acid sequence of SEQ ID NO: 19 with a mutation of the amino acid at position 84 to aspartic acid, a mutation of the amino acid at position 147 to valine, and a mutation of the amino acid at position 151 to serine.
17. The method of claim 1 , wherein the therapeutic protein comprises the amino acid sequence of SEQ ID NO: 19 with a mutation of the amino acid at position 83 to serine.
18. The method of claim 1 , wherein the therapeutic protein comprises the amino acid sequence of SEQ ID NO: 19 with a mutation of the amino acid at position 83 to serine, a mutation of the amino acid at position 147 to valine, and a mutation of the amino acid at position 151 to serine.
19. The method of claim 1 , wherein the therapeutic protein comprises the amino acid sequence of SEQ ID NO: 19 with a mutation of the amino acid at position 53 to serine.
20. The method of claim 1 , wherein the therapeutic protein comprises the amino acid sequence of SEQ ID NO: 19 with a mutation of the amino acid at position 53 to serine, a mutation of the amino acid at position 84 to aspartic acid, a mutation of the amino acid at position 147 to valine, and a mutation of the amino acid at position 151 to serine.
21. The method of claim 1 , wherein the therapeutic protein comprises the amino acid sequence of SEQ ID NO: 19 with a mutation of the amino acid at position 53 is serine, a mutation of the amino acid at position 83 to serine, a mutation of the amino acid at position 147 to valine, and a mutation of the amino acid at position 151 to serine.
22. The method of claim 1 , wherein the therapeutic protein comprises the amino acid sequence of SEQ ID NO: 19 with a mutation of the amino acid at position 147, the amino acid at position 151, the amino acid at position 83, and/or the amino acid at position 53.
23. The method of claim 1 , wherein the disorder is Crohn's disease or ulcerative colitis.
24. The method of claim 1 , wherein the therapeutic protein comprises a polypeptide encoded by the nucleic acid sequence of SEQ ID NO: 20.