Methods of enhancing functioning of the large intestine

Abstract

The invention relates to glucagon-related peptides and their use for the prevention or treatment of disorders involving the large intestine. In particular, it has now been demonstrated that GLP-2 and peptidic agonists of GLP-2 can cause proliferation of the tissue of large intestine. Thus, the invention provides methods of proliferating the large intestine in a subject in need thereof. Further, the methods of the invention are useful to treat or prevent inflammatory conditions of the large intestine, including inflammatory bowel diseases.

1 - 14 . (canceled) 
     
     
         15 . A method for treating a subject to enhance functioning of the large intestine comprising the step of delivering to the large intestine of the subject an effective amount of an intestinotrophic GLP-2 analog of SEQ ID NO: 1, wherein
 a) position 2 of the analog is an amino acid other than Ala,   b) positions 1, 4, 6, 7, 9, 12-15, 17-23, 25-27, and 29-33 of the analog correspond to the amino acids of SEQ ID NO: 1;   c) position 3 of the analog is optionally an amino acid other than Asp, wherein the amino acid other than Asp confers relative resistance to DPP-IV mediated cleavage;   d) position 5 of the analog is optionally an amino acid other than Ser;   e) position 8 of the analog is optionally an amino acid other than Asp;   f) position 10 of the analog is optionally an amino acid other than Met;   g) position 16 of the analog of SEQ ID NO: 1 optionally consists of an amino acid other than Asn; and   h) position 28 of the analog is optionally an amino acid other than Gln.   
     
     
         16 . The method of  claim 15 , wherein the subject is suffering from, or at risk of developing, an inflammatory condition involving the large intestine. 
     
     
         17 . The method of  claim 15 , wherein the subject has undergone partial or subtotal resection of the large intestine. 
     
     
         18 . The method of  claim 15 , wherein the analog is delivered to the large intestine by oral, subcutaneous, or rectal administration. 
     
     
         19 . The method of  claim 15 , wherein the substitutions within the analog are non-conservative substitutions. 
     
     
         20 . The method of  claim 15 , wherein the analog comprises Ala2Gly, Asp3Glu, Ser5Thr, Asp8Ser, Met10Leu, Asn16Ala, Asn24Ala, and Gln28Ala. 
     
     
         21 . The method of  claim 15 , wherein the analog comprises Ala2Gly, Asp3Glu, Asp8Ser, Met10Leu, Asn16Ala, Asn24Ala, and Gln28Ala. 
     
     
         22 . The method of  claim 15 , wherein the analog comprises an N-terminal or C-terminal extension. 
     
     
         23 . The method of  claim 22 , wherein the analog comprises a C-terminal extension. 
     
     
         24 . A method for treating a subject having, or at risk of developing, a condition in which functioning of the large intestine is impaired to enhance functioning of the large intestine comprising the steps of:
 a) obtaining an intestinotrophic GLP-2 analog of SEQ ID NO: 1, wherein
 i. position 2 of the analog is an amino acid other than Ala; 
 ii. positions 1, 4, 6, 7, 9, 12-15, 17-23, 25-27, and 29-33 of the analog correspond to the amino acids of SEQ ID NO: 1; 
 iii. position 3 of the analog is optionally an amino acid other than Asp, wherein the amino acid other than Asp confers relative resistance to DPP-IV mediated cleavage; 
 iv. position 5 of the analog is optionally an amino acid other than Ser; 
 v. position 8 of the analog is optionally an amino acid other than Asp; 
 vi. position 10 of the analog is optionally an amino acid other than Met; 
 vii. position 16 of the analog is optionally an amino acid other than Asn; 
 viii. position 24 of the analog is optionally an amino acid other than Asn; 
 ix. position 28 of the analog is optionally an amino acid other than Gln; and 
   b) delivering the analog to the large intestine of the subject in an amount effective to ameliorate the condition.   
     
     
         25 . The method of  claim 24 , wherein the subject is suffering from, or at risk of developing, an inflammatory condition involving the large intestine. 
     
     
         26 . The method of  claim 24 , wherein the subject has undergone partial or subtotal resection of the large intestine. 
     
     
         27 . The method of  claim 24 , wherein the analog is delivered to the large intestine by oral, subcutaneous, or rectal administration. 
     
     
         28 . The method of  claim 24 , wherein the analog comprises non-conservative substitutions. 
     
     
         29 . The method of  claim 24 , wherein the analog comprises Ala2Gly, Asp3Glu, Ser5Thr, Asp8Ser, Met10Leu, Asn16Ala, Asn24Ala, and Gln28Ala. 
     
     
         30 . The method of  claim 24 , wherein the analog comprises Ala2Gly, Asp3Glu, Asp8Ser, Met10Leu, Asn16Ala, Asn24Ala, and Gln28Ala. 
     
     
         31 . The method of  claim 24 , wherein the analog comprises an N-terminal or C-terminal extension. 
     
     
         32 . The method of  claim 31 , wherein the analog comprises a C-terminal extension. 
     
     
         33 . A kit for use in treating a subject having, or at risk of developing, a condition in which functioning of the large intestine is impaired to enhance functioning of the large intestine comprising:
 a) a lyophilized formulation of a GLP-2 analog of SEQ ID NO: 1 comprising intestinotrophic activity, wherein
 i. position 2 of the analog is an amino acid other than Ala; 
 ii. positions 1, 4, 6, 7, 9, 12-15, 17-23, 25-27, and 29-33 of the analog correspond to amino acids of SEQ ID NO: 1; 
 iii. position 3 of the analog of SEQ ID NO: 1 is optionally an amino acid other than Asp, wherein the amino acid other than Asp confers relative resistance to DPP-IV mediated cleavage, 
 iv. position 5 of the analog is optionally an amino acid other than Ser; 
 v. position 8 of the analog is optionally an amino acid other than Asp; 
 vi. position 10 of the analog is optionally an amino acid other than Met; 
 vii. position 16 of the analog is optionally an amino acid other than Asn; 
 viii. position 24 of the analog is optionally an amino acid other than Asn; 
 ix. position 28 of the analog is optionally an amino acid other than Gln; 
   b) a vial of sterile water for reconstitution; and   c) instructions directing reconstitution.   
     
     
         34 . The kit according to  claim 33 , comprising an injection device.