Method for the treatment of neurological disorders by enhancing the activity of beta-glucocerebrosidase
Provided is a method of increasing the stability of wild-type β-glucocerebrosidase. Also provided are methods of treating and/or preventing an individual having a neurological disease in which increased expression or activity of β-glucocerebrosidase in the central nervous system would be beneficial. This method includes administering an effective amount of a pharmacologic chaperone for β-glucocerebrosidase, with the proviso that the individual does not have a mutation in the gene encoding β-glucocerebrosidase. Further provided are β-glucocerebrosidase inhibitors which have been identified as specific pharmacologic chaperones and which have been shown to increase activity of β-glucocerebrosidase in vivo in the central nervous system.
1. A method for treating an alpha-synucleinopathy in an individual having or at risk of developing an alpha-synucleinopathy, wherein the individual does not have a mutation in the gene encoding beta-glucocerebrosidase, comprising administering to the individual (i) a pharmacological chaperone that binds to beta-glucocerebrosidase in an amount effective to treat the alpha-synucleinopathy, wherein treating the alpha-synucleinopathy comprises increasing the activity of β-glucocerebrosidase and thereby modulate the levels of alpha-synuclein and (ii) a second therapeutic agent, wherein the pharmacological chaperone is an isofagomine compound or derivative thereof.
2. The method of claim 1 , wherein the second therapeutic agent is a substrate inhibitor for GCase.
3. The method of claim 2 , wherein the substrate inhibitor is N-butyldeoxynojirimycin.
4. The method of claim 1 , wherein the second therapeutic agent is an anti-inflammatory agent.
5. The method of claim 4 , wherein the anti-inflammatory agent is ibuprofen or other NSAID.
6. The method of claim 1 , wherein the second therapeutic agent is dextromethorphan, genistein, or minocycline.
7. The method of claim 1 , wherein the second therapeutic agent is selected from the group consisting of RNAi, levodopa, an anticholinergic, a Catechol-O-methyl transferase inhibitor, a dopamine receptor agonist, a monoamine oxidase inhibitor, and a peripheral decarboxylase inhibitor.
8. The method of claim 1 , wherein the second therapeutic agent comprises inhibitory RNA (siRNA) for the SNCA gene.
9. The method of claim 1 , wherein the second therapeutic agent comprises gene therapy for the GBA gene.
10. The method of claim 1 , wherein the second therapeutic agent is a pharmacological chaperone for another lysosomal enzyme.
11. The method of claim 1 , wherein the second therapeutic agent is a vaccine comprising alpha-syn and an adjuvant.
12. The method of claim 1 , wherein the second therapeutic agent is a chaperone for alpha-syn.
13. The method of claim 12 , wherein the chaperone for alpha-syn is Hsp70.
14. The method of claim 1 , wherein the pharmacological chaperone is a competitive inhibitor of β-glucocerebrosidase.
15. The method of claim 1 , wherein the pharmacological chaperone is isofagomine tartrate.
16. The method of claim 1 , wherein the α-synucleinopathy is selected from the group consisting of Parkinson's disease, Lewy Body Disease, Multiple System Atrophy, Hallervorden-Spatz disease, and Frontotemporal Dementia.
17. The method of claim 1 , wherein the α-synucleinopathy is Parkinson's disease.