Method for the treatment of neurological disorders by enhancing the activity of β-glucocerebrosidase
View Patent ↗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 comprises 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 a neurodegenerative disorder in an individual having or at risk of developing a neurodegenerative disorder, wherein the individual does not have a mutation in the gene encoding β-glucocerebrosidase and wherein the neurodegenerative disorder is an α-synucleinopathy, which method comprises administering to the individual a pharmacological chaperone that reversibly binds to the active site of β-glucocerebrosidase in an amount effective to treat the α-synucleinopathy, wherein treating the α-synucleinopathy comprises increasing the activity of β-glucocerebrosidase and thereby modulating levels of α-synuclein.
2. 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, Hallervarden-Spatz disease, and Frontotemporal Dementia.
3. The method of claim 1 , wherein the pharmacological chaperone is a competitive inhibitor of β-glucocerebrosidase.
4. The method of claim 3 , wherein the pharmacological chaperone is an isofagomine compound.
5. The method of claim 4 , wherein the pharmacological chaperone is isofagomine tartrate.
6. The method of claim 1 , wherein the effective amount of the pharmacological chaperone increases the activity of β-glucocerebrosidase by at least 1.2-fold over basal levels.
7. The method of claim 6 , which comprises administering the pharmacological chaperone in an amount effective to increase the activity of β-glucocerebrosidase by at least 1.5-fold over basal levels.
8. The method of claim 7 , which comprises administering the pharmacological chaperone in an amount effective to increase the activity of β-glucocerebrosidase by at least 2-fold over basal levels.
9. The method of claim 1 , wherein the effective amount of the pharmacological chaperone modulates levels of α-synuclein in plasma of the individual.
10. The method of claim 1 , further comprising co-administering the pharmacological chaperone with a second therapeutic agent.
11. The method of claim 10 , wherein the neurodegenerative disorder is Parkinson's disease, parkinsonism or Lewy Body Dementia and the second therapeutic agent is selected from the group consisting of levodopa, an anticholinergic, a Catechol-O-methyl transferase (COMT) inhibitor, a dopamine receptor agonist, a monoamine oxidase inhibitor (MAO I), a peripheral decarboxylase inhibitor, and an anti-inflammatory.
12. The method of claim 1 , wherein the α-synucleinopathy is selected from the group consisting of Parkinson's disease, Lewy Body Disease and Multiple System Atrophy.
13. The method of claim 1 , wherein the α-synucleinopathy is Parkinson's disease.