Method for preventing and treating diabetes using neurturin

Abstract

The present invention relates generally to methods for preventing and/or treating pancreatic disorders, particularly those related to diabetes, by administering a neurturin protein product.

1 - 64 . (canceled) 
     
     
         65 . A method for stimulating and/or inducing the differentiation of insulin-producing cells from progenitor cells comprising contacting said progenitor cells with a neurturin product; wherein said neurturin product comprises a biologically active neurturin polypeptide; wherein said biologically active neurturin polypeptide is capable of dimerizing with another neurturin polypeptide and activating RET signaling; and wherein said biologically active neurturin polypeptide shares at least 90% sequence identity with:
 a) the human neurturin precursor protein having the amino acid sequence set forth in SEQ ID NO: 7; or   b) the mature neurturin protein product that results from the cleavage of the human neurturin protein precursor having an amino acid sequence set forth in SEQ ID NO: 7.   
     
     
         66 . The method of  claim 65 , wherein said progenitor cells are in vitro or ex vivo. 
     
     
         67 . The method of  claim 65 , wherein said progenitor cells are in a mammal having impaired beta-cell function, and wherein said contacting comprises administering said neurturin product to said mammal. 
     
     
         68 . The method of  claim 67 , wherein said mammal is also administered an immunosuppressive agent. 
     
     
         69 . The method of  claim 68 , wherein said neurturin product and said immunosuppressive agent are coadministered. 
     
     
         70 . The method of  claim 68 , wherein said neurturin product and said immunosuppressive agent are administered to said mammal separately. 
     
     
         71 . A method for normalizing blood glucose levels in a mammal having impaired beta-cell function, comprising the step of:
 administering a neurturin product to said mammal in an amount sufficient to increase neurturin concentration relative to an untreated mammal having impaired beta-cell function, wherein the levels of blood glucose are normalized in said mammal administered the neurturin product; wherein the neurturin product comprises a biologically active neurturin polypeptide; wherein the biologically active neurturin polypeptide is capable of dimerizing with another neurturin polypeptide and activating RET signaling; and wherein the biologically active neurturin polypeptide shares at least 90% sequence identity with:   a) the human neurturin precursor protein having the amino acid sequence set forth in SEQ ID NO: 7; or   b) the mature neurturin protein product that results from the cleavage of the human neurturin protein precursor having an amino acid sequence set forth in SEQ ID NO: 7.   
     
     
         72 . A method for generating insulin-producing cells from progenitor cells comprising the steps of:
 a) obtaining embryonic stem (ES) cells expressing a Pax4 gene; and   b) culturing said Pax4-expressing ES cells in the presence of a neurturin product, wherein said neurturin product comprises a biologically active neurturin polypeptide; wherein said biologically active neurturin polypeptide is capable of dimerizing with another neurturin polypeptide and activating RET signaling; and wherein said biologically active neurturin polypeptide shares at least 90% sequence identity with:
 i) the human neurturin precursor protein having the amino acid sequence set forth in SEQ ID NO: 7; or 
 ii) the mature neurturin protein product that results from the cleavage of the human neurturin protein precursor having an amino acid sequence set forth in SEQ ID NO: 7; 
   wherein culturing said Pax-4 expressing ES cells in the presence of said neurturin product stimulates and/or induces differentiation of insulin-producing cells.   
     
     
         73 . A method for generating insulin-producing cells from progenitor cells, comprising the steps of:
 a) contacting cells that express a pancreatic gene with a neurturin product; wherein the neurturin product comprises a biologically active neurturin polypeptide; wherein the biologically active neurturin polypeptide is capable of dimerizing with another neurturin polypeptide and activating RET signaling; and wherein the biologically active neurturin polypeptide shares at least 90% sequence identity with:
 i) the human neurturin precursor protein having the amino acid sequence set forth in SEQ ID NO: 7; or 
 ii) the mature neurturin protein product that results from the cleavage of the human neurturin protein precursor having an amino acid sequence set forth in SEQ ID NO: 7; and 
   b) culturing said pancreatic gene-expressing cells in the presence of said neurturin product;   wherein culturing said pancreatic gene-expressing cells in the presence of said neurturin product stimulates and/or induces differentiation of insulin-producing cells.   
     
     
         74 . The method of  claim 65 , wherein the biologically active neurturin polypeptide shares at least 95% sequence identity with:
 a) the human neurturin precursor protein having the amino acid sequence set forth in SEQ ID NO: 7; or   b) the mature neurturin protein product that results from the cleavage of the human neurturin protein precursor having an amino acid sequence set forth in SEQ ID NO: 7.   
     
     
         75 . The method of  claim 71 , wherein the biologically active neurturin polypeptide shares at least 95% sequence identity with:
 a) the human neurturin precursor protein having the amino acid sequence set forth in SEQ ID NO: 7; or   b) the mature neurturin protein product that results from the cleavage of the human neurturin protein precursor having an amino acid sequence set forth in SEQ ID NO: 7.   
     
     
         76 . The method of  claim 72 , wherein the biologically active neurturin polypeptide shares at least 95% sequence identity with:
 a) the human neurturin precursor protein having the amino acid sequence set forth in SEQ ID NO: 7; or   b) the mature neurturin protein product that results from the cleavage of the human neurturin protein precursor having an amino acid sequence set forth in SEQ ID NO: 7.   
     
     
         77 . The method of  claim 73 , wherein the biologically active neurturin polypeptide shares at least 95% sequence identity with:
 a) the human neurturin precursor protein having the amino acid sequence set forth in SEQ ID NO: 7; or   b) the mature neurturin protein product that results from the cleavage of the human neurturin protein precursor having an amino acid sequence set forth in SEQ ID NO: 7.   
     
     
         78 . The method of  claim 71 , wherein said mammal is also administered an immunosuppressive agent. 
     
     
         79 . The method of  claim 78 , wherein said neurturin product and said immunosuppressive agent are coadministered. 
     
     
         80 . The method of  claim 78 , wherein said neurturin product and said immunosuppressive agent are administered to said mammal separately. 
     
     
         81 . The method of  claim 67 , wherein said mammal having impaired beta-cell function suffers from diabetes type I. 
     
     
         82 . The method of  claim 71 , wherein said mammal having impaired beta-cell function suffers from diabetes type I. 
     
     
         83 . The method of  claim 67 , wherein said mammal having impaired beta-cell function suffers from diabetes type II. 
     
     
         84 . The method of  claim 71 , wherein said mammal having impaired beta-cell function suffers from diabetes type II. 
     
     
         85 . The method of  claim 67 , wherein said mammal having impaired beta-cell function suffers from latent autoimmune diabetes in adults. 
     
     
         86 . The method of  claim 71 , wherein said mammal having impaired beta-cell function suffers from latent autoimmune diabetes in adults.