Compositions and methods for regulated protein expression in gut

Abstract

The invention provides compositions and methods useful for treating disorders treatable by producing a protein in a regulatable manner in a mucosal cell or tissue of an animal. The treatment methods include in vivo and ex vivo methods, including transplanting in vitro transformed cells that secrete the protein into a mammalian subject.

1 .- 70 . (canceled) 
     
     
         71 . A method of treating diabetes, undesirable body mass or obesity in a mammalian subject comprising contacting gastrointestinal mucosal tissue cells in the subject with a polynucleotide vector comprising a promoter in operable linkage with a nucleic acid encoding GLP-1, wherein said contacting occurs in vivo via delivery to stomach or small intestine, thereby producing transformed gastrointestinal mucosal tissue cells wherein orally feeding the subject an amount of glucose, sucrose, fructose, carbohydrate, polypeptide, amino acid or fat increases transcription or secretion of the GLP-1 by the transformed cells in an amount effective to treat diabetes, undesirable body mass or obesity in the mammalian subject. 
     
     
         72 . The method of  claim 71 , wherein the diabetes comprises type 1 diabetes. 
     
     
         73 . The method of  claim 71 , wherein the subject has a fasting plasma glucose level greater than 110 mg/dl prior to treatment. 
     
     
         74 . The method of  claim 71 , wherein the diabetes comprises insulin-independent (type 2) diabetes. 
     
     
         75 . The method of  claim 71 , wherein the glucose increases transcription and secretion of the GLP-1 by the transformed cells. 
     
     
         76 . The method of  claim 71 , wherein the polypeptide or amino acid increases secretion of the GLP-1 by the transformed cells. 
     
     
         77 . The method of  claim 71 , wherein the promoter comprises glucose-dependent insulinotropic polypeptide (GIP) promoter or chromagranin A promoter. 
     
     
         78 . The method of  claim 77 , wherein the glucose-dependent insulinotropic polypeptide (GIP) or chromagranin A promoter comprises a functional variant or a functional subsequence thereof, and wherein the glucose-dependent insulinotropic polypeptide (GIP) or chromagranin A promoter functional variant or subsequence retains all or a part of non-variant or full-length glucose-dependent insulinotropic polypeptide (GIP) or chromagranin A promoter transcription function. 
     
     
         79 . The method of  claim 71 , wherein the gastrointestinal mucosal tissue cells are present in the small intestine. 
     
     
         80 . The method of  claim 71 , wherein the K cells, stem cells, multipotent progenitor cells or enteroendocrine cells are present in the stomach. 
     
     
         81 . The method of  claim 71 , wherein said contacting produces transformed K cells or transformed enteroendocrine cells. 
     
     
         82 . The method of  claim 71 , wherein the vector comprises a viral vector. 
     
     
         83 . The method of  claim 71 , wherein said contacting in vivo is with an endoscope, feeding tube, cannula, or catheter. 
     
     
         84 . The method of  claim 71 , wherein said contacting in vivo occurs orally. 
     
     
         85 . The method of  claim 71 , wherein said vector comprises a vector that facilitates integration of the nucleic acid encoding insulin into the genome of said K cells, stem cells, multipotent progenitor cells or enteroendocrine cells. 
     
     
         86 . The method of  claim 71 , wherein the subject is obese. 
     
     
         87 . A method of treating a blood coagulation disorder in a mammalian subject comprising contacting gastrointestinal mucosal cells in the subject with a polynucleotide vector comprising a promoter in operable linkage with a nucleic acid encoding a clotting factor, wherein said contacting occurs in vivo via delivery to stomach or small intestine, thereby producing transformed gastrointestinal mucosal cells, wherein orally feeding the subject an amount of glucose, sucrose, fructose, carbohydrate, polypeptide, amino acid or fat increases transcription or secretion of the clotting factor by the transformed cells in an amount effective to treat the blood coagulation disorder in the mammalian subject.