Mouse model and treatment of hereditary inclusion body myopathy

Abstract

Disclosed herein are methods of treating HIBM in a subject comprising identifying subject in need thereof; and administering to the subject a compound, or a pharmaceutically acceptable salt, ester, amide, glycol, peptidyl, or prodrug thereof, wherein the compound is a compound that is biosynthesized in a wild type individual along a biochemical pathway between glucose and sialic acid, inclusive. Also disclosed herein are vectors comprising a nucleic acid sequence that encodes a polypeptide having at least 80% sequence identity to the sequence set forth in SEQ ID NO:2, recombinant cells comprising these vectors, and recombinant animals comprising the cells. In addition, methods of identifying a compound having therapeutic effect for HIBM are disclosed.

What is claimed is: 
     
         1 . A vector comprising a nucleic acid sequence that encodes a polypeptide having at least 80% sequence identity to the sequence set forth in SEQ ID NO:2. 
     
     
         2 . The vector of  claim 1 , wherein the polypeptide has a sequence selected from the group consisting of set forth in SEQ ID NO:2 through SEQ ID NO:19. 
     
     
         3 . A recombinant cell comprising the vector wherein the vector comprises a nucleic acid sequence that encodes a polypeptide having at least 80% sequence identity to the sequence set forth in SEQ ID NO:2. 
     
     
         4 . The cell of  claim 3 , wherein the polypeptide has a sequence selected from the group consisting of set forth in SEQ ID NO:2 through SEQ ID NO:19. 
     
     
         5 . The cell of  claim 3 , wherein the cell is a stem cell. 
     
     
         6 . The cell of  claim 5 , wherein the cell is an embryonic stem cell. 
     
     
         7 . The cell of  claim 5 , wherein the cell is murine. 
     
     
         8 . A recombinant animal wherein the animal has a cell that expresses a polypeptide having at least 80% sequence identity to the sequence set forth in SEQ ID NO:2. 
     
     
         9 . The animal of  claim 8 , wherein the animal is made by the process of:
 producing a vector comprising a nucleic acid sequence that encodes a polypeptide having at least 80% sequence identity to the sequence set forth in SEQ ID NO:2;   producing a recombinant mammalian embryonic stem cell by infecting a mammalian embryonic stem cell with the vector;   selecting the embryonic stem cell line that has undergone homologous recombination to incorporate the vector sequence at a desired genomic locus;   planting the recombinant stem cell in an embryo;   implanting the embryo in a female animal; and   allowing the implanted embryo to mature into a fully formed fetus and be born from the female animal.   
     
     
         10 . The animal of  claim 8 , wherein the polypeptide has a sequence selected from the group consisting of set forth in SEQ ID NO:2 through SEQ ID NO:19. 
     
     
         11 . The animal of  claim 8 , wherein the animal comprises two alleles of the gene that encodes a polypeptide having a sequence set forth in SEQ ID NO:2. 
     
     
         12 . The animal of  claim 8 , wherein the animal comprises one allele of the gene that encodes a polypeptide having a sequence set forth in SEQ ID NO:2, and another allele of the gene that encodes a polypeptide having a sequence set forth in SEQ ID NO:3-19. 
     
     
         13 . The animal of  claim 8 , wherein the animal comprises two alleles of the gene that each independently encodes a polypeptide having a sequence set forth in SEQ ID NO:3-19. 
     
     
         14 . A method of identifying a compound having therapeutic effect for Hereditary Inclusion Body Myopathy (HIBM), the method comprising:
 administering the compound to a recombinant cell; and   measuring the effect of the compound on a rate of production, or an extent of production, of sialic acid or CMP-sialic acid by the cell,   wherein the recombinant cell comprising a nucleic acid sequence that encodes a polypeptide having at least 80% sequence identity to the sequence set forth in SEQ ID NO:2.   
     
     
         15 . The method of  claim 14 , wherein the recombinant cell comprises the vector, wherein the vector comprises a nucleic acid sequence that encodes a polypeptide having at least 80% sequence identity to the sequence set forth in SEQ ID NO:2. 
     
     
         16 . The method of  claim 14 , wherein the polypeptide has a sequence selected from the group consisting of set forth in SEQ ID NO:2 through SEQ ID NO:19. 
     
     
         17 . The method of  claim 14 , wherein the recombinant cell is in vitro. 
     
     
         18 . The method of  claim 14 , wherein the recombinant cell is a cell of a recombinant animal. 
     
     
         19 . The method of  claim 18 , wherein the recombinant cell is in vivo. 
     
     
         20 . The method of  claim 19 , wherein the recombinant animal is made by the process of:
 producing a vector comprising a nucleic acid sequence that encodes a polypeptide having at least 80% sequence identity to the sequence set forth in SEQ ID NO:2;   producing a recombinant mammalian embryonic stem cell by infecting a mammalian embryonic stem cell with the vector;   selecting the embryonic stem cell line that has undergone homologous recombination to incorporate the vector sequence at a desired genomic locus;   planting the recombinant stem cell in an embryo;   implanting the embryo in a female animal; and   allowing the implanted embryo to mature into a fully formed fetus and be born from the female animal.