Transgenic pig islets and uses thereof for treating diabetes

Abstract

The present invention relates to an isolated transgenic pig beta cell wherein the PKC and the PKA pathway are constitutively activated; to a transgenic pig islet comprising said transgenic pig beta cell; and to a transgenic pig comprising said transgenic pig beta cell or said transgenic pig islet. Another object of the invention is a device comprising a transgenic pig beta cell or a transgenic pig islet of the invention. The present invention also relates to the use of said transgenic pig beta cell, said transgenic pig islet, or said device for treating a disease, disorder or condition related to the impaired function of endocrine pancreas or of beta cell.

1 . An isolated transgenic pig beta cell wherein the PKC and the PKA pathway are constitutively activated. 
     
     
         2 . The isolated transgenic pig beta cell according to  claim 1 , wherein the cell comprises a constitutively active acetylcholine receptor. 
     
     
         3 . The isolated transgenic pig beta cell according to  claim 1 , wherein the cell comprises a constitutively active muscarinic receptor. 
     
     
         4 . The isolated transgenic pig beta cell according to  claim 1 , wherein the cell comprises a constitutively active type III muscarinic receptor. 
     
     
         5 . The isolated transgenic pig beta cell according to  claim 1 , wherein the cell comprises a constitutively active type III muscarinic receptor having an amino acid sequence SEQ ID NO: 4, or a sequence having at least 70% sequence identity with SEQ ID NO: 4. 
     
     
         6 . The isolated transgenic pig beta cell according to  claim 1 , wherein the cell expresses GLP-1. 
     
     
         7 . The isolated transgenic pig beta cell according to  claim 1 , wherein the cell expresses GLP1 having the amino acid sequence SEQ ID NO: 6, or a sequence having at least 70% sequence identity with SEQ ID NO: 6. 
     
     
         8 . An isolated transgenic pig islet comprising a pig beta cell according to  claim 1 . 
     
     
         9 . An ex vivo method for obtaining an isolated transgenic pig beta cell according to  claim 1  or an isolated transgenic pig islet comprising a said isolated transgenic pig beta cell, wherein said method uses an expression vector comprising a nucleic acid sequence encoding a constitutively active type III muscarinic receptor, and an expression vector comprising a nucleic acid sequence encoding GLP-1. 
     
     
         10 . An isolated transgenic pig beta cell or an isolated transgenic pig islet obtained by the method according to  claim 9 . 
     
     
         11 . A transgenic pig comprising an isolated transgenic pig beta cell according to  claim 1 , or an isolated transgenic pig islet comprising a said isolated transgenic pig beta cell. 
     
     
         12 . A device comprising an isolated transgenic pig beta cell according to  claim 1  or an isolated transgenic pig islet comprising an said isolated transgenic pig beta cell. 
     
     
         13 . The device according to  claim 12 , wherein said isolated transgenic pig beta cell or said isolated transgenic pig islet are encapsulated in an alginate composition. 
     
     
         14 . A method for treating a disease, disorder or condition related to the impaired function of endocrine pancreas or beta cell in a subject in need thereof, comprising administering an isolated transgenic pig beta cell according to  claim 1  or an isolated transgenic pig islet comprising a said isolated transgenic pig beta cell, or a device comprising a said isolated transgenic pig beta cell or isolated transgenic pig islet. 
     
     
         15 . The method according to  claim 14 , wherein said disease, disorder or condition related to the impaired function of endocrine pancreas or beta cell is selected from the group comprising type I diabetes, type II diabetes, gestational diabetes, latent autoimmune diabetes, type 1.5 diabetes, lipoatrophic diabetes, maturity onset diabetes of the young, neonatal diabetes, prediabetes, steroid-induced diabetes, and pancreatic cancer. 
     
     
         16 . The method according to  claim 14 , wherein said disease, disorder or condition related to the impaired function of endocrine pancreas or beta cell is permanent neonatal diabetes or transient neonatal diabetes. 
     
     
         17 . The method according to  claim 14 , wherein said disease, disorder or condition related to the impaired function of endocrine pancreas or beta cell is an endocrine pancreas cancer. 
     
     
         18 . The method according to  claim 14 , wherein said disease, disorder or condition related to the impaired function of endocrine pancreas or beta cell is an endocrine pancreatic tumor or a pancreatic neuroendocrine carcinoma.