Compositions and Methods for Treating Disorders Associated with Abnormal Phosphate Metabolism

Abstract

The present invention uncovers that mutations in GALNT3 gene encoding UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase (GalNAc-T3) cause familial tumoral calcinosis (FTC). Methods and pharmaceutical compositions useful for treating disorders associated with abnormal phosphate metabolism are provided. Specifically, inducers of GalNAc-T3 can be used to treat hyperphosphatemia related disorders such as FTC, and on the other hand, inhibitors of GalNAc-T3 can be used to treat disorders associated with hypophosphatemia, such as hypophosphatemic rickets. The present invention further provides methods and kits for diagnosing familial tumoral calcinosis as well as for identifying agents suitable for treating disorders associated with abnormal phosphate metabolism.

1 - 34 . (canceled) 
     
     
         35 . A method of treating a disorder associated with abnormal phosphate metabolism comprising providing to an individual in need thereof an agent capable of regulating an expression level and/or activity of GalNAc-T3, thereby treating the disorder associated with abnormal phosphate metabolism in said individual. 
     
     
         36 . The method of  claim 35 , wherein said disorder is associated with hyperphosphatemia. 
     
     
         37 . The method of  claim 36 , wherein said disorder associated with hyperphosphatemia is selected from the group consisting of familial tumoral calcinosis (FTC), hyperphosphatemic calcinosis, hemodialysis and chronic renal failure. 
     
     
         38 . The method of  claim 35 , wherein said regulating is upregulating said expression level and/or activity of said GalNAc-T3, said upregulating is effected by an agent selected from the group consisting of:
 (a) an exogenous polynucleotide encoding at least a functional portion of GALNT3;   (b) an agent capable of increasing expression of endogenous GalNAc-T3 in an individual;   (c) an agent capable of increasing endogenous GalNAc-T3 activity in an individual;   (d) an exogenous polypeptide including at least a functional portion of GalNAc-T3;   (e) a GalNAc-T3 substrate; and   (f) a GalNAc-T3-expressing cell.   
     
     
         39 . The method of  claim 38 , wherein said exogenous polynucleotide encoding at least a functional portion of GALNT3 is set forth in SEQ ID NO:29. 
     
     
         40 . The method of  claim 35 , wherein said disorder is associated with hypophosphatemia. 
     
     
         41 . The method of  claim 40 , wherein said disorder associated with said hypophosphatemia is selected from the group consisting of X-linked vitamin D resistant hypophosphatemic rickets (HYP), hereditary hypercalciuria with hypophosphatemic rickets (HHRH), oncogenic hypophosphatemic osteomalacia (OHO) and X-linked hypophosphatemic rickets (PHEX). 
     
     
         42 . The method of  claim 35 , wherein said regulating is downregulating said expression level and/or said activity of said GalNAc-T3, said downregulating is effected by an agent selected from the group consisting of:
 (a) a molecule which binds said GalNAc-T3;   (b) an enzyme which cleaves said GalNAc-T3;   (c) an antisense polynucleotide capable of specifically hybridizing with at least part of an mRNA transcript encoding GALNT3;   (d) a ribozyme which specifically cleaves at least part of an mRNA transcript encoding GALNT3;   (e) a small interfering RNA (siRNA) molecule which specifically cleaves at least part of a transcript encoding GALNT3;   (f) a non-functional analogue of at least a catalytic or binding portion of said GalNAc-T3;   (g) a molecule which prevents GalNAc-T3 activation or substrate binding.   
     
     
         43 . The method of  claim 42 , wherein said mRNA transcript encoding GALNT3 is set forth in SEQ ID NO:29. 
     
     
         44 . A method of diagnosing familial tumoral calcinosis (FTC) in an individual, the method comprising identifying in a polynucleotide sequence of the individual at least one nucleic acid substitution resulting in downregulation of an expression level and/or activity of GalNAc-T3, thereby diagnosing familial tumoral calcinosis in the individual. 
     
     
         45 . The method of  claim 44 , wherein said polynucleotide sequence is an mRNA sequence encoding GALNT3 or a genomic sequence region including the GALNT3 gene. 
     
     
         46 . A method of diagnosing familial tumoral calcinosis in an individual, the method comprising identifying in a polypeptide sequence of the individual at least one amino acid substitution capable of downregulating expression level and/or activity of GalNAc-T3, thereby diagnosing familial tumoral calcinosis in the individual. 
     
     
         47 . The method of  claim 46 , wherein said polypeptide sequence is set forth in SEQ ID NO:28. 
     
     
         48 . The method of  claim 46 , wherein said identifying said at least one amino acid substitution is effected using an antibody capable of differentially binding to at least one polymorph of said GalNAc-T3, said at least one polymorph includes said amino acid substitution capable of downregulating said expression level and/or said activity of GalNAc-T3. 
     
     
         49 . A kit for diagnosing familial tumoral calcinosis in an individual, the kit comprising a packaging material packaging at least one reagent and instructions for use in diagnosing familial tumoral calcinosis, said at least one reagent for identifying in a polynucleotide sequence of the individual at least one nucleic acid substitution resulting in downregulation of an expression level and/or activity of GalNAc-T3, thereby diagnosing familial tumoral calcinosis in the individual. 
     
     
         50 . The kit of  claim 49 , wherein said polynucleotide sequence is an mRNA sequence encoding GALNT3 or a genomic sequence region including the GALNT3 gene. 
     
     
         51 . A kit for diagnosing familial tumoral calcinosis in an individual, the kit comprising a packaging material packaging at least one reagent and instructions for use in diagnosing familial tumoral calcinosis, said at least one reagent for identifying in a polypeptide sequence of the individual at least one amino acid substitution capable of downregulating expression level and/or activity of GalNAc-T3, thereby diagnosing familial tumoral calcinosis in the individual. 
     
     
         52 . The kit of  claim 51 , wherein said polypeptide sequence is set forth in SEQ ID NO:28. 
     
     
         53 . The kit of  claim 51 , wherein said reagent for identifying said at least one amino acid substitution comprises an antibody capable of differentially binding to at least one polymorph of said GalNAc-T3, said at least one polymorph includes said amino acid substitution capable of downregulating said expression level and/or said activity of GalNAc-T3.