Treatment of CNS disorders associated with mutations in genes encoding lysosomal enzymes
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. A method for treating Parkinson's disease in an individual, which method comprises administering to the individual an effective amount of C-benzyl isofagomine.
2. The method of claim 1 , wherein the C-benzyl isofagomine is effective to prevent or reduce neuronal or extraneuronal accumulation of α-synuclein.
3. The method of claim 1 , wherein the individual is homozygous for a mutation in the gene encoding β-glucocerebrosidase.
4. The method of claim 1 , wherein the individual is homozygous, hemizygous, heterozygous or compound heterozygous for a mutation in the gene encoding β-glucocerebrosidase.
5. The method of claim 4 , wherein the individual is heterozygous or homozygous for an N370S mutation.
6. The method of claim 4 , wherein the individual is heterozygous for an 84GG mutation.
7. The method of claim 4 , wherein the individual is heterozygous for an R496H mutation.
8. The method of claim 4 , wherein the mutation is a conformational mutant.
9. The method of claim 8 , wherein the C-benzyl isofagomine increases trafficking of the mutant enzyme from the endoplasmic reticulum and/or restores enzyme activity.
10. The method of claim 1 , wherein the individual is hemizygous, heterozygous or compound heterozygous for a mutation in the gene encoding β-glucocerebrosidase.