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Funded Studies

Treatment of Parkinson’s Disease with AT2101, a compound that increases the activity of endogenous Glucocerebrosidase

Genetic association studies have suggested a link between Parkinson's and Gaucher disease. Gaucher disease is a lysosomal storage disorder caused by mutations in the gene GBA, which results in a loss of glucocerebrosidase (GCase) enzyme activity and a toxic accumulation of glucosylceramide in the lysosomes. Several studies have found an over-representation of GBA mutations among patient's with Parkinson's disease (up to 14 percent in non-Jewish populations and 30 percent in Ashkenazi Jews). In further support of a link between these two diseases, we have identified an animal model for Gaucher disease that also accumulates alpha-synuclein and develops a progressive tremor. Parkinson's disease is strongly associated with the neuronal accumulation of alpha-synuclein. Alpha-synuclein is degraded, in part, by the lysosome, which contains hydrolytic enzymes, such as GCase, involved in the degradation of cellular waste.

Pharmacological chaperones are small molecules that can be administered orally. One such chaperone, AT2101, increases both mutant and normal GCase activities by stabilizing GCase in the endoplasmic reticulum and promoting trafficking of the enzyme to the lysosome. AT2101 is currently in clinical trials for the treatment of Gaucher disease. Under the proposed research plan, we will use AT2101 to increase GCase enzyme activity in two pre-clinical models that accumulate alpha-synuclein. The first pre-clinical model has a mutation that decreases GCase activity, the second has normal GCase enzyme. We hypothesize that increasing the activity of GCase enzyme will indirectly improve the cell's ability to keep the accumulation of alpha-synuclein in check. Together these models will provide a test of AT2101 efficacy for the reduction of alpha-synuclein in both Gaucher-associated and idiopathic Parkinson's.

Final Outcome

In year one, Amicus developed intriguing efficacy data for AT2101 in an animal model of PD. Year two focused on improving our understanding of the appropriate dosing of AT2101. Drs. Wustman and Clark have tested their lead compound in animal models of PD. Final results indicated some promising results with AT2101 and Amicus launched an internal PD drug development program based on these findings.

These pilot studies were followed by more extensive investigations, extending the AT2101 treatment period from 12 to 26 weeks and testing in additional PD animal models. The possibility of reduction of synuclein in the brain was also explored in a pre-clinical model of Gaucher disease that accumulates synuclein.

While AT2101 proved effective in the initial mouse studies, we have now discovered new compounds that improve upon the properties of AT2101 in ways that may be important for the treatment of PD rather than Gaucher disease. The new compounds, developed specifically for Parkinson’s, are currently being tested in additional PD-related animal models.

Success with the pre-clinical Parkinson’s disease program has led to the exploration of Pharmacological Chaperones for other diseases of neurodegeneration.


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