Compositions and methods for treating disease associated with permeability of intestinal epithelium

Abstract

The present invention provides methods for treating disorders associated with intestinal barrier dysfunction and increased intestinal permeability. The invention involves administering an effective amount larazotide or a larazotide derivative to a subject or a patient in need thereof.

1 . A method for treating a subject having or at risk of necrotizing enterocolitis (NEC), comprising administering an effective amount larazotide or a larazotide derivative to the subject. 
     
     
         2 . A method for treating a subject having an ischemic intestinal condition, comprising administering an effective amount larazotide or a larazotide derivative to the subject. 
     
     
         3 . A method for treating a subject having or at risk of sepsis, comprising administering an effective amount larazotide or a larazotide derivative to the subject. 
     
     
         4 . A method of treating a subject having or at risk of a liver condition selected from nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and cirrhosis (e.g., alcohol cirrhosis), comprising administering an effective amount larazotide or a larazotide derivative to the subject. 
     
     
         5 . The method of  claim 1 , wherein the NEC is stage I, stage II NEC, stage M NEC, or advanced NEC. 
     
     
         6 . The method of  claim 2 , wherein the subject has ischemic colitis or intestinal volvulus. 
     
     
         7 . The method of  claim 6 , wherein the ischemic colitis is mild to moderate. 
     
     
         8 . The method of  claim 6 , wherein the ischemic colitis is severe. 
     
     
         9 . The method of  claim 4 , wherein the subject has a fatty liver disease resulting from hepatitis, obesity, diabetes, insulin resistance, hypertriglyceridemia, abetalipoproteinemia, glycogen storage disease, Weber-Christian disease, Wolmans disease, acute fatty liver of pregnancy, and lipodystrophy. 
     
     
         10 . The method of any one of  claims 1  to  9 , comprising administering an effective amount of larazotide or salt thereof. 
     
     
         11 . The method of any one of  claims 1  to  9 , comprising administering an effective amount of a larazotide derivative or salt thereof. 
     
     
         12 . The method of  claim 10  or  11 , wherein the larazotide or derivative is administered in a sustained release or controlled release formulation. 
     
     
         13 . The method of  claim 12 , wherein the sustained release or controlled release formulation releases from 0.5 to about 5 mg of larazotide or derivative over the course of at least about 2 hours. 
     
     
         14 . The method of  claim 13 , wherein the sustained release or controlled release formulation contains at least 1 mg of larazotide or derivative. 
     
     
         15 . The method of  claim 14 , wherein the sustained release or controlled release formulation releases larazotide or derivative over at least 210 minutes of exposure to simulated intestinal fluid. 
     
     
         16 . The method of any one of  claims 1  to  15 , wherein the composition comprising larazotide or derivative is administered to the small intestine. 
     
     
         17 . The method of  claim 16 , wherein the larazotide or derivative is released in one or more of the duodenum, jejunum and ileum. 
     
     
         18 . The method of  claim 16  or  17 , wherein the larazotide or derivative is released in one or more of the colon transversum, colon descendens, colon ascendens, colon sigmoidenum and cecum. 
     
     
         19 . The method of any one of  claims 1  to  18 , wherein the composition comprising larazotide or derivative is administered more than once daily. 
     
     
         20 . The method of any one of  claims 1  to  19 , further comprising, administering antibiotic therapy. 
     
     
         21 . The method of any one of  claims 1  to  19 , further comprising, administering antiviral therapy. 
     
     
         22 . The method of any one of  claims 1  to  19 , further comprising administering probiotic.