Treatment of CNS Disorders Associated with Mutations in Genes Encoding Lysosomal Enzymes

Abstract

Described is a method for treating an individual having a neurological disorder with an associated mutation or mutations in a gene encoding a lysosomal enzyme. Specifically, the individual is administered a specific pharmacological chaperone for the lysosomal enzyme which increases trafficking of the protein from the ER to the lysosome in neural cells, with or without concomitantly increasing enzyme activity in neural cells. Restoration of trafficking relieves cell stress and other toxicities associated with accumulation of mutant proteins. Restoration of enzyme activity relieves substrate accumulation and pathologies associated with lipid accumulation. In a specific embodiment, the neurological disorder is Parkinson's disease or parkinsonism which is associated with mutations in glucocerebrosidase.

1 - 20 . (canceled) 
     
     
         21 . A method for treating a neurodegenerative disorder in an individual having or at risk of developing an a-synucleinopathy, wherein the individual has a mutation in the gene encoding β-glucocerebrosidase, which method comprises
 administering to the individual an effective amount of an isofagomine derivative that reversibly binds to β-glucocerebrosidase. 
 
     
     
         22 . The method of  claim 21 , wherein the isofagomine derivative is effective to prevent or reduce neuronal or extraneuronal accumulation of α-synuclein. 
     
     
         23 . The method of  claim 21 , wherein the α-synucleinopathy is Parkinson's or parkinsonism. 
     
     
         24 . The method of  claim 21 , wherein the individual is homozygous for the mutation. 
     
     
         25 . The method of  claim 21 , wherein the individual is hemizygous, heterozygous or compound heterozygous for the mutation. 
     
     
         26 . The method of  claim 25 , wherein the individual is heterozygous for an 84GG mutation. 
     
     
         27 . The method of  claim 25 , wherein the individual is heterozygous for an R496H mutation. 
     
     
         28 . The method of  claim 21 , wherein the individual is heterozygous or homozygous for an N370S mutation. 
     
     
         29 . The method of  claim 21 , wherein the mutation is a conformational mutant. 
     
     
         30 . The method of  claim 29 , wherein the pharmacological chaperone increases trafficking of the mutant enzyme from the endoplasmic reticulum and/or restores enzyme activity. 
     
     
         31 . A method for treating Parkinson's or parkinsonism, wherein the individual has a mutation in the gene encoding β-glucocerebrosidase, which method comprises
 administering to the individual an effective amount of a pharmacological chaperone that reversibly binds to β-glucocerebrosidase. 
 
     
     
         32 . The method of  claim 31 , wherein the pharmacological chaperone e is effective to prevent or reduce neuronal or extraneuronal accumulation of α-synuclein. 
     
     
         33 . The method of  claim 31 , wherein the pharmacological chaperone is isofagomine or an isofagomine derivative. 
     
     
         34 . The method of  claim 31 , wherein the pharmacological chaperone is isofagomine. 
     
     
         35 . The method of  claim 31 , wherein the pharmacological chaperone is C-benzyl isofagomine. 
     
     
         36 . The method of  claim 31 , wherein the individual is homozygous for the mutation. 
     
     
         37 . The method of  claim 31 , wherein the individual is hemizygous, heterozygous or compound heterozygous for the mutation. 
     
     
         38 . The method of  claim 37 , wherein the individual is heterozygous for an 84GG mutation. 
     
     
         39 . The method of  claim 37 , wherein the individual is heterozygous for an R496H mutation. 
     
     
         40 . The method of  claim 31 , wherein the individual is heterozygous or homozygous for an N370S mutation.