GT-02287, a clinical-stage GCase enhancer, improves activities of daily living and cognitive performance in a preclinical model of GBA1 Parkinson’s disease

The aim of this study was to investigate the ability of GT-02287 to rescue nest-building behaviour following delayed administration in a mouse model of GBA1-Parkinson's disease (GBA1-PD). Nest building is a non-invasive test to study activities of daily living and cognitive performance in rodent models. GT-02287 is an orally bioavailable, brain penetrant, small-molecule structurally targeted allosteric regulator that binds to glucocerebrosidase (GCase), stabilizes it, and increases its function by chaperoning it to the lysosome. It is currently in Phase 1 clinical development for the treatment of GBA1-PD. C57BL/6 mice underwent low-level chronic intraperitoneal administration of irreversible GCase inhibitor, conduritol beta-epoxide (CBE), for 28 days combined with intrastriatal injection of alpha-synuclein preformed fibrils (PFFs) on day 1 to model GBA1-PD. GT-02287 was administrated orally once daily starting 8 days after the initial toxic insult. Nest-building performance was assessed at various times and plasma NfL levels were assessed by ELISA on the day of sacrifice. We show that, in this delayed treatment paradigm, GT-02287 improves nest-building performance in a mouse model of GBA1-PD and that this is correlated with a reduction of plasma levels of NfL, an emerging biomarker of neurodegeneration. This suggests that GT-02287 can rescue complex behaviours in which cognitive function is involved, in addition to an improvement in motor function reported previously. These data further support the potential of GT-02287 as a disease-modifying therapy for the treatment of GBA1-PD that is already clinically established, including improvement in activities of daily living and cognition.