Methods and Compositions for the Treatment of Gastrointestinal Disorders

Abstract

Compositions and related methods for treating IBS and other gastrointestinal disorders and conditions (e.g., gastrointestinal motility disorders, functional gastrointestinal disorders, gastroesophageal reflux disease (GERD), duodenogastric reflux, Crohn's disease, ulcerative colitis, inflammatory bowel disease, functional heartburn, dyspepsia (including functional dyspepsia or nonulcer dyspepsia), gastroparesis, chronic intestinal pseudo-obstruction (or colonic pseudoobstruction), and disorders and conditions associated with constipation, e.g., constipation associated with use of opiate pain killers, post-surgical constipation, and constipation associated with neuropathic disorders as well as other conditions and disorders are described. The compositions feature peptides that activate the guanylate cyclase C (GC-C) receptor.

1 - 52 . (canceled) 
     
     
         53 . A purified polypeptide comprising the amino acid sequence Asn Asp Glu Cys Glu Leu Cys Val Asn Val Ala Cys Thr Gly Cys Leu (SEQ ID NO:73), wherein one or two amino acids are substituted by a D-isomer of the amino acid. 
     
     
         54 . The purified polypeptide of  claim 53 , wherein two amino acids are substituted by the D-isomer of the amino acid. 
     
     
         55 . A purified polypeptide consisting of the amino acid sequence Asn Asp Glu Cys Glu Leu Cys Val Asn Val Ala Cys Thr Gly Cys Leu (SEQ ID NO:73), wherein one or two amino acids are substituted by a D-isomer of the amino acid. 
     
     
         56 . The purified polypeptide of  claim 55 , wherein two amino acids are substituted by the D-isomer of the amino acid. 
     
     
         57 . A pharmaceutical composition comprising a polypeptide according to  claim 53  and a pharmaceutically acceptable carrier. 
     
     
         58 . A method for treating a patient with a gastrointestinal disorder, the method comprising administering to the patient the pharmaceutical composition of  claim 57 . 
     
     
         59 . The method of  claim 58 , wherein the gastrointestinal disorder is selected from the group consisting of a gastrointestinal motility disorder, irritable bowel syndrome, constipation, a functional gastrointestinal disorder, gastroesophageal reflux disease, functional heartburn, dyspepsia, functional dyspepsia, nonulcer dyspepsia, gastroparesis, chronic intestinal pseudo-obstruction, colonic pseudo-obstruction, Crohn's disease, ulcerative colitis or inflammatory bowel disease. 
     
     
         60 . The method of  claim 59 , wherein the gastrointestinal disorder is dyspepsia, functional dyspepsia or nonulcer dyspepsia. 
     
     
         61 . The method of  claim 60 , wherein the gastrointestinal disorder is functional dyspepsia. 
     
     
         62 . The method of  claim 59 , wherein the gastrointestinal disorder is ulcerative colitis, Crohn's disease or inflammatory bowel disease. 
     
     
         63 . The method of  claim 62 , wherein the gastrointestinal disorder is ulcerative colitis. 
     
     
         64 . The method of  claim 59 , wherein the gastrointestinal disorder is irritable bowel syndrome. 
     
     
         65 . The method of  claim 64 , wherein the irritable bowel syndrome is constipation-predominant irritable bowel syndrome (c-IBS). 
     
     
         66 . The method of  claim 59 , wherein the gastrointestinal disorder is constipation. 
     
     
         67 . The method of  claim 66 , wherein the constipation is idiopathic constipation. 
     
     
         68 . The method of  claim 59 , wherein the gastrointestinal disorder is gastroparesis. 
     
     
         69 . A method for increasing gastrointestinal motility in a patient, the method comprising administering to the patient the pharmaceutical composition of  claim 57 . 
     
     
         70 . A method for decreasing gastrointestinal pain or visceral pain in a patient, the method comprising administering to the patient the pharmaceutical composition of  claim 57 . 
     
     
         71 . A method for treating a patient suffering from constipation-predominant irritable bowel syndrome, the method comprising orally administering to the patient a composition comprising a polypeptide consisting of the amino acid sequence Asn Asp Glu Cys Glu Leu Cys Val Asn Val Ala Cys Thr Gly Cys Leu (SEQ ID NO: 73), wherein one or two amino acids are substituted by the D-isomer of the amino acid. 
     
     
         72 . The method of  claim 71 , wherein the polypeptide consists of two amino acids substituted by the D-isomer of the amino acid. 
     
     
         73 . A method for treating a patient suffering from constipation, the method comprising orally administering to the patient a composition comprising a polypeptide consisting of the amino acid sequence Asn Asp Glu Cys Glu Leu Cys Val Asn Val Ala Cys Thr Gly Cys Leu (SEQ ID NO: 73), wherein one or two amino acids are substituted by the D-isomer of the amino acid. 
     
     
         74 . The method of  claim 73 , wherein the polypeptide consists of two amino acids substituted by the D-isomer of the amino acid. 
     
     
         75 . A method for treating obesity, the method comprising administering to a patient a composition comprising a polypeptide consisting of the amino acid sequence Asn Asp Glu Cys Glu Leu Cys Val Asn Val Ala Cys Thr Gly Cys Leu (SEQ ID NO: 73), wherein one or two amino acids are substituted by the D-isomer of the amino acid. 
     
     
         76 . A method for treating a patient with a gastrointestinal disorder, the method comprising administering to the patient a purified polypeptide comprising the amino acid sequence Pro Gly Thr Cys Glu Ile Cys Ala Tyr Ala Ala Cys Thr Gly Cys (SEQ ID NO:4), wherein one or two amino acids are substituted by a D-isomer of the amino acid. 
     
     
         77 . The method of  claim 76 , wherein the gastrointestinal disorder is selected from the group consisting of a gastrointestinal motility disorder, irritable bowel syndrome, constipation, a functional gastrointestinal disorder, gastroesophageal reflux disease, functional heartburn, dyspepsia, functional dyspepsia, nonulcer dyspepsia, gastroparesis, chronic intestinal pseudo-obstruction, colonic pseudo-obstruction, Crohn's disease, ulcerative colitis or inflammatory bowel disease. 
     
     
         78 . The method of  claim 77 , wherein the gastrointestinal disorder is dyspepsia, functional dyspepsia or nonulcer dyspepsia. 
     
     
         79 . The method of  claim 77 , wherein the gastrointestinal disorder is ulcerative colitis, Crohn's disease or inflammatory bowel disease. 
     
     
         80 . The method of  claim 77 , wherein the gastrointestinal disorder is irritable bowel syndrome. 
     
     
         81 . The method of  claim 77 , wherein the gastrointestinal disorder is constipation. 
     
     
         82 . The method of  claim 77 , wherein the gastrointestinal disorder is gastroparesis. 
     
     
         83 . A method for increasing gastrointestinal motility in a patient, the method comprising administering to the patient a purified polypeptide comprising the amino acid sequence Pro Gly Thr Cys Glu Ile Cys Ala Tyr Ala Ala Cys Thr Gly Cys (SEQ ID NO:4), wherein one or two amino acids are substituted by a D-isomer of the amino acid. 
     
     
         84 . A method for decreasing gastrointestinal pain or visceral pain in a patient, the method comprising administering to the patient a purified polypeptide comprising the amino acid sequence Pro Gly Thr Cys Glu Ile Cys Ala Tyr Ala Ala Cys Thr Gly Cys (SEQ ID NO:4), wherein one or two amino acids are substituted by a D-isomer of the amino acid. 
     
     
         85 . A method for treating a patient suffering from constipation-predominant irritable bowel syndrome, the method comprising orally administering to the patient a composition comprising a polypeptide consisting of the amino acid sequence Pro Gly Thr Cys Glu Ile Cys Ala Tyr Ala Ala Cys Thr Gly Cys (SEQ ID NO:4), wherein one or two amino acids are substituted by the D-isomer of the amino acid. 
     
     
         86 . The method of  claim 85 , wherein the polypeptide consists of two amino acids substituted by the D-isomer of the amino acid. 
     
     
         87 . A method for treating a patient suffering from constipation, the method comprising orally administering to the patient a composition comprising a polypeptide consisting of the amino acid sequence Pro Gly Thr Cys Glu Ile Cys Ala Tyr Ala Ala Cys Thr Gly Cys (SEQ ID NO:4), wherein one or two amino acids are substituted by the D-isomer of the amino acid. 
     
     
         88 . The method of  claim 87 , wherein the polypeptide consists of two amino acids substituted by the D-isomer of the amino acid. 
     
     
         89 . A method for treating obesity, the method comprising administering to a patient a composition comprising a polypeptide consisting of the amino acid sequence Pro Gly Thr Cys Glu Ile Cys Ala Tyr Ala Ala Cys Thr Gly Cys (SEQ ID NO:4), wherein one or two amino acids are substituted by the D-isomer of the amino acid. 
     
     
         90 . A method of producing a polypeptide consisting of the amino acid sequence Asn Asp Glu Cys Glu Leu Cys Val Asn Val Ala Cys Thr Gly Cys Leu (SEQ ID NO:73), wherein one or two amino acids are substituted by the D-isomer of the amino acid, the method comprising providing a cell harboring a nucleic acid molecule encoding the polypeptide, culturing the cell under conditions in which the polypeptide is expressed, and isolating the expressed polypeptide. 
     
     
         91 . A method of producing a polypeptide consisting of the amino acid sequence Asn Asp Glu Cys Glu Leu Cys Val Asn Val Ala Cys Thr Gly Cys Leu (SEQ ID NO:73), the method comprising chemically synthesizing the polypeptide and then purifying the synthesized polypeptide. 
     
     
         92 . A method of producing a polypeptide consisting of the amino acid sequence Pro Gly Thr Cys Glu Ile Cys Ala Tyr Ala Ala Cys Thr Gly Cys (SEQ ID NO:4), wherein one or two amino acids are substituted by the D-isomer of the amino acid, the method comprising providing a cell harboring a nucleic acid molecule encoding the polypeptide, culturing the cell under conditions in which the polypeptide is expressed, and isolating the expressed polypeptide. 
     
     
         93 . A method of producing a polypeptide consisting of the amino acid sequence Pro Gly Thr Cys Glu Ile Cys Ala Tyr Ala Ala Cys Thr Gly Cys (SEQ ID NO:4), the method comprising chemically synthesizing the polypeptide and then purifying the synthesized polypeptide.