Overview

Name: GT-02287
Therapy Type: Small Molecule (timeline)
Target Type: alpha-synuclein, Other (timeline)
Condition(s): Parkinson's Disease
U.S. FDA Status: Parkinson's Disease (Phase 1)
Company: Gain Therapeutics, Inc.

Background

GT-02287 is a brain-penetrant, small molecule allosteric regulator of the lysosomal enzyme glucocerebrosidase (GCase). Mutations in the GBA1 gene encoding GCase are the most common genetic cause of Parkinson’s disease. Reduced GCase activity impairs lysosomal function and leads to accumulation of misfolded α-synuclein. GCase activity is also lower in sporadic Parkinson’s cases, suggesting that restoring GCase activity could be a viable strategy for the treatment of both genetic and non-genetic forms of the disease.

As an allosteric modulator, GT-02287 binds at a location removed from the active site to enhance protein stability and enzymatic activity. It was discovered using computational methods to design drug candidates based on the atomic structure of human GCase. GT-02287 was shown to enhance GCase activity in cells from patients with Gaucher disease or GBA1 Parkinson’s (Montpeyo et al., 2024). In cell models, GT-02287 enhanced lysosomal activity and reduced cellular stress (Fregno et al., 2025).

According to preclinical results presented at the April 2025 AD/PD conference, GT-02287 improved motor function and coordination in mouse models of GBA1 PD and sporadic PD. Treatment restored normal nest-building behaviors, which enlist both cognitive and motor skills. Effects on behavior began to be seen within hours after drug administration. Both fast (within two hours) and persistent (after 29 days) actions of the drug were associated with higher GCase activity, enhanced lysosomal and mitochondrial function, and elevated dopamine levels in the brain, as well as reduced ER stress and neuronal cell death. Improvements in movement and nesting behaviors persisted for 30 days after drug dosing was stopped, suggesting a disease-modifying effect. Treatment was associated with persistent reduction in aggregated α-synuclein, and brain biomarkers of microgliosis and astrogliosis.

Findings

In July 2024, a Phase 1 study in healthy adults was completed in Australia. The placebo-controlled trial tested single doses of 1.4, 4.8, 7.7, 10, and 12 mg/kg, taken as a drink of powder suspended in water. Multiple dosing included 1.4, 4.8, 7.7, or 10 mg/kg/day for two weeks. According to an August 2024 press release, GT-02287 was safe and tolerable, yielded the expected plasma and CSF exposure, and resulted in a greater than 50 percent increase in GCase activity at clinically useful doses.

In February 2025, a Phase 1b study began to assess safety and tolerability in people with Parkinson’s disease with or without GBA1 mutations. The open-label study will enroll 20 participants to receive an oral dose of 13.5 mg/kg once daily for three months. The study is also evaluating pharmacokinetics in blood and CSF, and changes in motor and cognitive symptoms, and daily function. Other endpoints include GCase activity in blood, as well as sphingolipids, α-synuclein, and inflammatory markers in CSF. The study will run at seven sites in Australia until November 2025.

For details on this trial, see clinicaltrials.gov.

Last Updated: 06 Jun 2025

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References

Paper Citations

Montpeyo M, Pérez-Carmona N, Cubero E, Delgado A, Ruano A, Carrillo J, Bellotto M, Martinez-Vicente M, Garcia-Collazo AM. Developing Allosteric Chaperones for GBA1-Associated Disorders-An Integrated Computational and Experimental Approach. Int J Mol Sci. 2024 Dec 24;26(1) PubMed.
Fregno I, Pérez-Carmona N, Rudinskiy M, Soldà T, Bergmann TJ, Ruano A, Delgado A, Cubero E, Bellotto M, García-Collazo AM, Molinari M. Allosteric Modulation of GCase Enhances Lysosomal Activity and Reduces ER Stress in GCase-Related Disorders. Int J Mol Sci. 2025 May 6;26(9) PubMed.

Therapeutics

GT-02287

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