Treatment and detection of inherited neuropathies and associated disorders

Abstract

The present disclosure relates to methods of detecting and treating inherited neuropathy.

1 . A method of treating inherited neuropathy in a mammalian subject, the method comprising:
 (a) detecting the presence of a mutation in the sorbitol dehydrogenase (SORD) gene in a sample from the subject; and   (b) administering to the subject a polynucleotide that encodes a SORD peptide, an aldose reductase antisense oligonucleotide, an agent that blocks expression of a mutant SORD gene, an agent that corrects the mutation in SORD gene, or a combination of any of the foregoing.   
     
     
         2 . The method of  claim 1 , wherein the method comprises administering a polynucleotide encoding the SORD peptide. 
     
     
         3 . The method of  claim 1 , wherein the method comprises administering an agent that corrects the mutation in the SORD gene, wherein the agent is a CRISPR Cas9 protein and one or more guide RNA molecules. 
     
     
         4 . A method of treating inherited neuropathy in a mammalian subject, the method comprising administering to the subject an aldose reductase inhibitor. 
     
     
         5 . A method of treating inherited neuropathy in a mammalian subject, the method comprising:
 (a) detecting the presence of a mutation in the sorbitol dehydrogenase (SORD) gene in a sample from the subject; and   (b) administering to the subject a SORD peptide.   
     
     
         6 . The method of  claim 1 , wherein the mutation in the SORD gene is c.753delG; p.Ala253GlnfsTer27, c.329G>C; p.Arg110Pro, c.298C>T; p.Arg100Ter, or c.458C>A; p.Ala153Asp. 
     
     
         7 . The method of  claim 1 , wherein the mutation in the SORD gene is c.757delG; p.Ala253GlnfsTer27, c.28C>T; p.Leu10Phe, c.316_425+165del; p.Cys106Ter, c.295C>T; p.Arg299Ter, c.964G>A; p.Val322Ile, or a deletion of individual or multiple coding exons or the entire SORD gene. 
     
     
         8 . The method of  claim 1 , further comprising measuring sorbitol in a sample from the subject. 
     
     
         9 . A method of characterizing a neuropathy in a mammalian subject, the method comprising measuring the level of sorbitol in a subject suffering from a neuropathy, wherein a sorbitol level of greater than about 10 g/L indicates that the neuropathy is associated with a mutation in the sorbitol dehydrogenase (SORD) gene. 
     
     
         10 . A method of evaluating the efficacy of a treatment for an inherited neuropathy in a subject, the method comprising
 administering to the subject an agent selected from the group consisting of an aldose reductase inhibitor, an aldose reductase antisense oligonucleotide, a polynucleotide that encodes a SORD peptide, a SORD peptide, an agent that blocks expression of a mutant SORD gene, and an agent that corrects the mutation in SORD gene, or a combination of any of the foregoing; and   measuring the level of sorbitol in a subject.   
     
     
         11 . The method of  claim 4 , comprising detecting the presence of a mutation in the sorbitol dehydrogenase (SORD) gene in a sample from the subject. 
     
     
         12 . The method of  claim 4 , wherein the aldose reductase inhibitor is selected from the group consisting of alrestatin, epalrestat, diepalrestat, fidarestat, imirestat, lidorestat, minalrestat, ponalrestat, ranirestat, salfredin B 11 , sorbinil, tolrestat, zenarestat, and zopolrestat. 
     
     
         13 . The method of  claim 5 , wherein the mutation in the SORD gene is c.753delG; p.Ala253GlnfsTer27, c.329G>C; p.Arg110Pro, c.298C>T; p.Arg100Ter, or c.458C>A; p.Ala153Asp. 
     
     
         14 . The method of  claim 5 , wherein the mutation in the SORD gene is c.757delG; p.Ala253GlnfsTer27, c.28C>T; p.Leu10Phe, c.316_425+165del; p.Cys106Ter, c.295C>T; p.Arg299Ter, c.964G>A; p.Val322Ile, or a deletion of individual or multiple coding exons or the entire SORD gene. 
     
     
         15 . The method of  claim 5 , further comprising measuring sorbitol in a sample from the subject. 
     
     
         16 . An adeno-associated viral (AAV) vector that encodes a SORD peptide. 
     
     
         17 . An isolated nucleic acid comprising an antisense oligonucleotide sequence listed in Table 2 or 16-18.