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GT-02287 reduces mitochondrial stress and enhances neuronal survival in MPP+ treated rat dopaminergic neurons
GT-02287 decreases staining for MIRO1, suggesting improved mitochondrial health in α-synuclein-induced mouse PD model
GT-02287 improves mitochondrial function by facilitating GCase trafficking to the mitochondria in patient-derived fibroblasts harboring GBA1 mutation
Gain Therapeutics, Inc. (Nasdaq: GANX) ("Gain", or the "Company"), a clinical-stage biotechnology company leading the discovery and development of the next generation of allosteric small molecule therapies, today announced a poster presentation was made at the Society for Neuroscience annual meeting, Neuroscience 2025, held November 15 th -19 th in San Diego, CA. The poster outlined new evidence from three preclinical models supporting the Company's lead drug candidate's, GT-02287, proposed mechanism of action of facilitating trafficking of glucocerebrosidase (GCase) to the mitochondria as well as the lysosomes, supporting its potential as a disease-modifying therapy for Parkinson's disease (PD).
"We are very encouraged by the preclinical data presented at Neuroscience 2025. In addition to adding to an already robust preclinical dossier, we believe the data further elucidate the mechanism of action of GT-02287 and suggests that it acts throughout the disease cascade resulting from dysfunctional glucocerebrosidase (GCase)," commented Joanne Taylor, Ph.D., Senior Vice President of Research of Gain. "Importantly, we continue to advance our understanding of GCase-mediated interactions in the disease pathology of Parkinson's disease and the role GCase enhancement plays in mitochondrial as well as lysosomal health."
Gene Mack, President and CEO of Gain, added, "Our confidence in GT-02287 grows with the mounting preclinical evidence of its broad neuroprotective effect on the biology of Parkinson's disease. The new data presented at Neuroscience 2025 demonstrates a direct impact on mitochondrial health, a previously open question from PD investigators regarding the mechanism of GT-02287 in dopaminergic neurons. This observation also adds to the previously reported evidence of GT-02287's beneficial effects in other important neuronal cell compartments such as the lysosome and endoplasmic reticulum that, in our view, are critically important to achieve broad neuroprotection in those with Parkinson's disease."
Mr. Mack continued, "We look forward to seeing how the effects on relevant pathway abnormalities that we have observed preclinically and in healthy volunteers translate to people with Parkinson's disease in our upcoming 90-day analysis, which will include biomarker activity in cerebrospinal fluid and blood."
The poster, titled, "GT-02287, a small molecule allosteric modulator of the lysosomal enzyme glucocerebrosidase (GCase), also affects GCase at the level of the mitochondria," was presented on-site by Joanne Taylor, Ph.D. The poster detailed three separate models.
In cultured rat mesencephalic dopaminergic neurons treated with MPP+, a mitochondrial toxin that induces mitochondrial impairment by inhibiting mitochondrial complex I, GT-02287 reduced mitochondrial reactive oxygen species and prevented cytochrome C release (a programmed cell death signal), thereby alleviating mitochondrial stress and promoting neuronal survival.
In a mouse PD model, in which α-synuclein pre-formed fibrils were injected into the striatum, GT-02287 decreased substantia nigral staining for mitochondrial protein MIRO1, a marker of depolarized mitochondria destined for mitophagy.
In patient-derived fibroblasts carrying the severe L444P GBA1 mutation, GT-02287 increased mitochondrial GCase levels, enhanced mitochondrial complex I activity, and improved mitochondrial membrane potential.
These findings together suggest that GT-02287 improves mitochondrial function by facilitating GCase trafficking to the mitochondria.
A PDF of the poster presented at Neuroscience 2025 is available on the Science and Technology section of the Company's website at https://gaintherapeutics.com/science-and-technology/posters .
About GT-02287
Gain Therapeutics' lead drug candidate, GT-02287, is in clinical development for the treatment of Parkinson's disease (PD) with or without a GBA1 mutation. The orally administered, brain-penetrant small molecule is an allosteric enzyme modulator that restores the function of the lysosomal enzyme glucocerebrosidase (GCase) which becomes misfolded and impaired due to mutations in the GBA1 gene, the most common genetic abnormality associated with PD, or other age-related stress factors. In preclinical models of PD, GT-02287 restored GCase enzymatic function, reduced ER stress, lysosomal and mitochondrial pathology, aggregated α-synuclein, neuroinflammation and neuronal death, as well as plasma neurofilament light chain (NfL) levels, a biomarker of neurodegeneration. In rodent models of both GBA1-PD and idiopathic PD, GT-02287 was shown to rescue deficits in motor function and gait and prevent the development of deficits in complex behaviors such as nesting.
Compelling preclinical data in models of both GBA1-PD and idiopathic PD, demonstrating a disease-modifying effect after administration of GT-02287, suggest that GT-02287 may have the potential to slow or stop the progression of Parkinson's disease.
Results from a Phase 1 study of GT-02287 in healthy volunteers demonstrated favorable safety and tolerability, plasma and CNS exposures in the projected therapeutic range, and target engagement with an increase in glucocerebrosidase (GCase) activity among those receiving GT-02287 at clinically relevant doses.
GT-02287 is currently being evaluated in a Phase 1b clinical trial for the treatment of Parkinson's disease with or without a GBA1 mutation. The primary endpoint of the trial, which enrolled participants across 7 sites in Australia, is to evaluate the safety and tolerability of GT-02287 after 3 months of dosing in people with Parkinson's disease. Early observations of exploratory endpoints suggest that GT-02287 has disease-modifying effects consistent with the proposed mechanism of action and seen in preclinical models in vivo. The recently commenced Phase 1b study extension allows participants to continue to be treated with GT-02287 for up to a total of 12 months.
Gain's lead program in Parkinson's disease has been awarded funding support early in its development from The Michael J. Fox Foundation for Parkinson's Research (MJFF) and The Silverstein Foundation for Parkinson's with GBA, as well as from the Eurostars-2 joint program with co-funding from the European Union Horizon 2020 research and Innosuisse – Swiss Innovation Agency.
About Gain Therapeutics, Inc.
Gain Therapeutics, Inc. is a clinical-stage biotechnology company leading the discovery and development of next generation allosteric therapies. Gain's lead drug candidate, GT-02287 is currently being evaluated for the treatment of Parkinson's disease with or without a GBA1 mutation in a Phase 1b clinical trial. GT-02287 has further potential in Gaucher's disease, dementia with Lewy bodies, and Alzheimer's disease. Gain has multiple undisclosed preclinical assets targeting lysosomal storage disorders, metabolic diseases, and solid tumors.
Gain's unique approach enables the discovery of novel, allosteric small molecule modulators that can restore or disrupt protein function. Deploying its highly advanced Magellan™ platform, Gain is accelerating drug discovery and unlocking novel disease-modifying treatments for untreatable or difficult-to-treat disorders including neurodegenerative diseases, rare genetic disorders and oncology.
Forward-Looking Statements
This release contains "forward-looking statements" made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements are typically preceded by words such as "believes," "expects," "anticipates," "intends," "will," "may," "should," or similar expressions. These forward-looking statements reflect management's current knowledge, assumptions, judgment and expectations regarding future performance or events. Although management believes that the expectations reflected in such statements are reasonable, they give no assurance that such expectations will prove to be correct or that those goals will be achieved, and you should be aware that actual results could differ materially from those contained in the forward-looking statements. Forward-looking statements are subject to a number of risks and uncertainties, including, but not limited to, statements regarding: the development of the Company's current or future product candidates including GT-02287; expectations regarding the completion and timing of results from a Phase 1b clinical study for GT-02287, including any extension studies; expectations regarding the timing of patient enrollment for a Phase 1b clinical study for GT-02287, including any extension studies; the timing of any submissions to the FDA or other regulatory bodies and agencies; and the potential therapeutic and clinical benefits of the Company's product candidates. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to the Company's business in general, please refer to the Company's Form 10-K for the year ended December 31, 2024. All forward-looking statements are expressly qualified in their entirety by this cautionary notice. You are cautioned not to place undue reliance on any forward-looking statements, which speak only as of the date of this release. We have no obligation, and expressly disclaim any obligation, to update, revise or correct any of the forward-looking statements, whether because of new information, future events or otherwise.
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