Objective: Demonstrate the involvement of our structurally targeted allosteric regulator Parkinson’s disease (PD) candidate, GT-02287, in decreasing the CBE-induced neurotoxic effect and in restoring lysosomal health in dopaminergic primary rat neurons and in CBE-treated mice.

Background: GBA1 encodes the lysosomal enzyme glucocerebrosidase (GCase), whose deficiency has been linked to increased alpha-synuclein pathology, as well as to lysosomal, mitochondrial and endoplasmic reticulum stress, key pathophysiological features in PD. Importantly, GBA1 mutations also increase the risk factor for sporadic PD.

Method: Gain Therapeutics applies its innovative proprietary drug discovery platform, Site-directed Enzyme Enhancement Therapy (SEE-Tx™), to the development of small-molecule structurally targeted allosteric regulators (STAR^s) that stabilize GCase avoiding its degradation whilst facilitating its maturation and trafficking to the lysosomes. GT-02287 is a small molecule identified by the SEE-Tx platform, that exhibits a good toxicology profile and enhances GCase activity and levels by promoting its stabilization.
CBE, a covalent inhibitor that reacts with the catalytic site of GBA and inactivates the enzyme, was used to cause a partial defect of GCase activity comparable to heterozygotes GBA-PD patients. CBE-based models represent an additional tool to study pathophysiological pathways in PD under GCase defect and are considered relevant for the development of treatments for the disease.

Results: We report in vitro and in vivo evidence showing pharmacological chaperone-mediated activity by our orally bioavailable and brain penetrant lead, GT-02287, in dopaminergic rat neurons injured with CBE and in chronically treated mice. This is shown as a counteracting effect of the CBE-induced neurotoxicity and as an improvement of the lysosomal health.

Conclusion: Enhancement of the lysosomal GCase activity by GT-02287 protects against key pathophysiological hallmarks of PD, including alpha-synuclein and lysosomal related pathology, ameliorating dopaminergic cells phenotype. Therefore, STAR^s therapy represents a novel pharmacological tool for the treatment of PD, warranting further development towards the clinic.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/gt-02287-a-brain-penetrant-structurally-targeted-allosteric-regulator-for-glucocerebrosidase-show-evidence-of-pharmacological-efficacy-in-conduritol-%ce%b2-epoxide-cbe-models-of-parkinsons/