Objective: To investigate the effect of the structurally targeted allosteric regulator GT-02287 on rotenone-induced neurotoxic effects in a Parkinson’s disease animal model.

Background: Mutations in the GBA1 gene, which encodes the lysosomal enzyme glucocerebrosidase (GCase), represent the most significant risk factor for PD development. Sporadic PD patients also exhibit GCase deficiency linked to α-synuclein and lysosomal pathology along with ER stress. The rat rotenone model is widely used to model PD and Rocha et al., 2020, demonstrated that rotenone administration impairs GCase and alters its glycolipid substrate levels. The rotenone model thus represents an optimal tool to study therapeutic interventions in the context of PD-GBA pathophysiology. Gain Therapeutics applied its innovative proprietary drug discovery platform, Site-directed Enzyme Enhancement Therapy (SEE-Tx®), to the development of small-molecule structurally targeted allosteric regulators (STARs) that stabilize GCase, avoiding its degradation and facilitating trafficking to the lysosomes. GT-02287 is a STAR compound that enhances GCase function and exhibits good CNS drug properties.

Method: Rats were treated with rotenone (2.5 mg/kg, i.p.) and GT-02287 (60 and 90 mg/kg p.o.) once a day for ten days.  Glucosylceramide levels were assessed by UHPLC-MS/MS. GCase, LAMP-1, aggregated α-synuclein, TNFα and tyrosine hydroxylase (TH) levels were assessed by immunostaining and confocal microscopy quantification.

Results: GT-02287 restored GCase levels, improved lysosomal health, and reduced toxic accumulation of glucosylceramide and aggregated alpha-synuclein after rotenone injury. In addition, GT-02287 reduced TNFα levels and increased TH immunostaining (a marker of dopaminergic neurons) in rotenone-injured-rats.

Conclusion: Augmentation of GCase function by GT-02287 protects against key pathophysiological hallmarks of PD, including alpha-synuclein and lysosomal pathology as well as neuroinflammation; ultimately increasing dopaminergic neuronal survival. GT-02287 emerges as a potential disease-modifying, first-in-class, orally available and brain penetrant therapy for PD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gt-02287-a-brain-penetrant-structurally-targeted-allosteric-regulator-for-glucocerebrosidase-shows-evidence-of-pharmacological-efficacy-in-an-animal-model-of-parkinsons-disease/