Researchers have implicated the disruption of glucocerebrosidase (GCase) activity, an enzyme involved in lipid breakdown, in neurodegeneration.1 Gain Therapeutics is pursuing a novel Parkinson’s disease (PD) treatment that helps restore the protein’s folding and trafficking.
Gene Mack
Chief Executive Officer
Gain Therapeutics
In this Innovation Spotlight, Gene Mack, the chief executive officer of Gain Therapeutics, discusses the company’s Magellan™ platform, which uss machine learning and structural modeling to identify allosteric pockets in enzymes, unlocking new druggable targets in previously inaccessible proteins. This strategy led to the discovery of GT-02287, an allosteric modulator of GCase, which is now in clinical trials for PD treatment.
What are some of the biggest challenges facing patients with PD?
Managing both the physical and non-motor symptoms that progressively impact their quality of life is a big challenge for patients. While tremors and mobility issues are well known, many patients also struggle with cognitive decline, mood disorders, sleep problems, and medication-related complications. These symptoms can lead to loss of independence, emotional distress, and a significant burden on caregivers. Importantly, current treatments only treat symptoms and do not prevent disease progression.
What role does GCase play in neurodegenerative diseases, and how can targeting the dysfunctional enzyme help alleviate disease?
GCase is a key enzyme involved in breaking down certain lipids within cells. It plays an integral role in organelle and cellular health. GCase depletes toxic lysosomal substrates and more recently has been found to stabilize mitochondrial respiratory complex I. In neurodegenerative diseases such as PD, reduced GCase activity—often due to mutations in the glucosylceramidase beta (GBA1) gene—leads to the accumulation of toxic substances that damage neurons.1 This contributes to inflammation, protein buildup (such as alpha-synuclein), and, ultimately, cell death. The aim of targeting and restoring GCase function is to improve the cell’s natural waste-clearing systems, reduce neuroinflammation, and slow or possibly halt disease progression.
What is Gain’s Magellan™ platform, and how has it been used to identify potential therapeutics?
The Magellan™ platform’s unique machine learning AI models evaluate the 3D structures of proteins and potential allosteric sites. By leveraging neural networks and physics-based molecular simulations, Magellan™ studies atomic positioning and dynamics to determine site interactions and ligand affinity. This allows scientists to predict the druggability of the allosteric pocket.
Targeting allosteric binding sites involves binding to a different part of a protein, any site that is not the active site, to modulate its function. Targeting allosteric binding sites expands the target universe to 90 percent of undruggable proteins and unlocks all mechanisms for protein target engagement. Binding to allosteric sites has the potential for higher specificity and may provide superior regulation of disease-implicated proteins.
Utilizing an automated, virtual screening methodology, Magellan™ can explore a vast chemical space of on-demand compound libraries with over 5 trillion compounds and identify proprietary, fit-for-purpose, structurally targeted allosteric regulator small molecule candidates.
By restoring GCase activity, GT-02287 can reduce neuroinflammation and other key drivers of neurodegeneration.
©iStock, image_jungle
What is GT-02287, and how does it work?
GT-02287 is a GCase chaperone that binds to defective GCase shortly after it is transcribed and corrects protein misfolding, helping chaperone it through its intracellular trafficking pattern. In preclinical models of PD, GT-02287 restored GCase enzymatic function and reduced ER stress, lysosomal and mitochondrial pathology, aggregated α-synuclein, neuroinflammation, neuronal death, and plasma neurofilament light chain (NfL) levels, a biomarker of neurodegeneration.
GT-02287 is differentiated from other investigational therapies targeting GCase in that it acts higher in the disease cascade as a chaperone, providing a broader neuroprotective effect. Other small molecule therapies increase only GCase in the lysosome, which we believe is insufficient to slow or stop disease progression.
In addition to PD, GT-02287 has potential in Alzheimer’s disease, dementia with Lewy bodies, and Gaucher’s disease.
Where are you in the clinical development of this drug, and what results have you seen so far?
Gain Therapeutics is currently running a Phase 1b study of GT-02287 in people with PD with or without a GBA1 mutation. A Phase 1b study extension allows participants to continue treatment for an additional nine months, and more than half of the participants have agreed to do so. Results from the Phase 1 healthy volunteer study, released in September 2024, demonstrated good safety and tolerability as well as target engagement of GCase. Specifically, the study found a 53 percent increase in GCase activity in healthy volunteers measured 12 hours post-dose on study day 14.
What is next on the horizon for GT-02287 and Gain Therapeutics?
In the fourth quarter of 2025, we expect a full 90-day analysis of the participants enrolled in the study through June 30, 2025. This includes functional changes scored according to the PD assessment Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) and biomarker activity in cerebrospinal fluid and blood. Our final results from the Phase 1b study extension are expected in the second half of 2026. We expect an investigational new drug application (IND) filing by the end of 2025 and a Phase 2 study in the first half of 2026. Planning of the Phase 2 study is underway.
- Chen Y, et al. Glucocerebrosidase as a therapeutic target for Parkinson’s disease. Expert Opin Ther Targets. 2020;24(4):287-294.
