Amicus Therapeutics Presents Preclinical Studies of Chaperone AT3375 for Gaucher Disease

AT3375 is a next-generation, small molecule pharmacological chaperone that targets the glucocerebrosidase (GCase) enzyme deficient in Gaucher disease, a mechanism with the potential to address Gaucher and Parkinson's. AT3375 was the lead compound selected from a series of chaperones designed by Amicus to improve upon the properties of AT2101 (isofagomine tartrate), a first-generation chaperone that Amicus was originally developing for Gaucher disease.
The oral presentation at LDN WORLD was titled, "Preclinical Results Exploring the Use of Pharmacological Chaperone AT3375 Alone and in Combination with Recombinant Human Beta-Glucosidase for Gaucher Disease." Key highlights were as follows:

In combination with ERT, AT3375 binds to and stabilizes the recombinant enzyme, minimizing its thermal denaturation and loss of activity in vitro.

AT3375 co-administered with ERT increased active enzyme in plasma and Gaucher-disease relevant tissues (liver, spleen and lung) compared to AT2101 co-administered with ERT. In addition, ERT co-administered with either chaperone increased enzyme activity compared to ERT alone. When used as a monotherapy, AT3375 increased GCase activity in patient-derived cells with greater potency compared to AT2101. In mouse models, higher levels of AT3375, orally administered as a monotherapy, were present in the brain and the compound was cleared more rapidly than AT2101. AT3375 increased brain GCase levels with greater potency compared to AT2101.

Recombinant GCase ERTs (imiglucerase and velaglucerase alfa) are current standard of therapy for Gaucher disease, however, they are unable to cross the blood-brain-barrier to address CNS aspects of the disease. These ERTs are also highly unstable outside the lysosome, and could potentially benefit from the presence of a small molecule chaperone that binds to and stabilizes recombinant enzyme.
David J. Lockhart, Chief Scientific Officer of Amicus Therapeutics said, "Our initial preclinical studies of AT3375 demonstrate the potential for chaperone-ERT co-administration to improve the properties of ERTs for Gaucher disease. These results also suggest that AT3375 can increase brain GCase levels, supporting our investigation of AT3375 to address Parkinson's disease by targeting GCase."

Gaucher disease is a lysosomal storage disorder caused by inherited genetic mutations in the GBA gene, which result in deficient activity of the GCase enzyme and lysosomal accumulation of glucocerebroside inside certain cells. Mutations in the GBA1 gene that encodes for the GCase enzyme are also the most common genetic risk factor known for Parkinson's disease. Gaucher disease affects an estimated 8,000 to 10,000 people worldwide. Gaucher patients have an estimated 20-fold increased risk of developing Parkinson's disease, and an estimated 5% to 10% of the diagnosed Parkinson's population are carriers of Gaucher disease.