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Home >> Programs >> Preclinical Programs
Preclinical Programs
Gaucher Disease and the Gaucher-Parkinson’s Link
Individuals with Gaucher disease have an estimated 20-fold increased risk of developing Parkinson's disease, and an estimated 5% to 10% of those diagnosed with Parkinson's are carriers of the Gaucher disease gene. Inherited genetic mutations in the GBA1 gene, which encodes for the glucocerebrosidase (GCase) enzyme, are the cause of Gaucher disease. Over the last decade, GBA1 mutations have also been identified as the most common genetic risk factor for Parkinson's.
Amicus has been a pioneer in investigating the link between Gaucher and Parkinson's disease. Over the past five years, Amicus has been developing pharmacological chaperones that target GCase as potential therapeutic agents for Gaucher and Parkinson’s diseases. Increasing the activity of GCase in the brain with a small-molecule pharmacological chaperone may reduce the negative consequences of carrying GBA1 mutations.
Chaperone-ERT Combinations for Gaucher Disease
Amicus is also exploring whether chaperone-ERT combinations can improve outcomes in Gaucher disease. GCase ERTs are the current standard of care therapy for Gaucher disease. However, ERT is based on the regular infusion of large protein molecules that are unable to cross the blood-brain-barrier to address central nervous system aspects of certain types of Gaucher disease as well as Parkinson’s. GCase ERTs also are highly unstable outside the lysosomes, especially at the neutral pH of blood, and could potentially benefit from the presence of a small molecule chaperone that binds to and stabilizes the infused enzyme.
The pharmacological chaperones AT3375 and AT2101 (afegostat tartrate) are small molecules that target the GCase enzyme. Amicus has investigated AT3375 and AT2101 alone and in combination with ERT in preclinical studies for Gaucher disease. These studies demonstrated that AT3375 or AT2101 co-administered with ERT to rodents increased the levels of active enzyme in plasma and Gaucher-disease relevant tissues (liver, spleen and lung) compared to ERT alone.
Pharmacological Chaperones for Parkinson’s Disease
AT3375 is a next-generation, small molecule pharmacological chaperone that targets the GCase enzyme in the brain. AT3375 was the lead compound selected from a series of chaperones designed by Amicus to improve upon the properties of AT2101, a first-generation chaperone previously developed as a monotherapy for Gaucher disease. Amicus and collaborators previously conducted studies of AT2101 in mice that were genetically engineered to overproduce α-synuclein, the protein that accumulates in Parkinson’s disease. Results demonstrated that AT2101 increased the activity of brain GCase, prevented accumulation of α-synuclein in the brain, and improved motor function as assessed in various behavioral tests. Following the completion of these studies, Amicus developed new compounds, including AT3375, which is more potent and has demonstrated improved target selectivity and brain penetration.
AT3375 is currently in preclinical studies that are funded in part by a grant from the Michael J. Fox Foundation. Preclinical studies of AT3375 for Gaucher disease suggest that this chaperone can increase brain GCase levels, supporting the investigation of AT3375 for Parkinson’s disease in Gaucher gene carrier’s and potentially the broader Parkinson’s population.
Other Chaperone-ERT Combinations for Lysosomal Storage Diseases
Amicus is investigating undisclosed chaperone-ERT combinations as potential next-generation treatments for additional lysosomal storage diseases where there are significant opportunities to improve treatment outcomes.
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Amicus Therapeutics has been a pioneer in investigating the link between Gaucher and Parkinson's disease.
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