Data Showcases Promising Mechanism of Action of GT-02287 for Parkinson Disease

Findings from a recent study displayed the mechanism of action of Gain Therapeutics’ GT-02287, an agent in development for the treatment of GBA1 Parkinson disease (PD), by boosting lysosomal glucocerebrosidase (GCase) activity.¹ Overall, the results suggested that the agent aids in the correct folding of GCase and prevents it from undergoing protein quality control-mediated endoplasmic reticulum (ER) retention and associated degradation.

Presented at the 2024 International Conference on Alzheimer’s and Parkinson’s Disease (AD/PD), held March 5-9, in Lisbon, Portugal, investigators observed that L444P GCase had an enhanced association with ER chaperones as well as bonded to calnexin and brain ischemic preconditioning (BiP) to greater extent than N370S through treatment with GT-02287. Notably, L444P GCase triggered an unfolded protein response (UPR) and fibroblasts of L444P GCase showed a higher level of the ER stress marker BiP.

Top Clinical Takeaways

New data suggests GT-02287 facilitates correct folding of GCase, preventing its retention and degradation, thus contributing to lysosomal and cellular health.
The study utilized patient-derived fibroblasts and a cell-based model to assess GCase function and transport to lysosomes, respectively.
These findings offer promising insights into the potential of GT-02287 as a treatment for GBA1 PD, presenting a differentiated approach to addressing the condition.

"The research confirms the mechanism of action of our clinical stage GCase modulator in that we were able to alleviate ER stress caused by mutated and misfolded protein getting stuck in the ER, avoid proteosomal degradation of the enzyme as part of the UPR, facilitate trafficking to the lysosome and increase lysosomal GCase activity and consequently reduce the buildup of GCase’s toxic lipid substrate, glucosyl ceremide, in the lysosome," Joanne Taylor, PhD, senior vice president of research at Gain Therapeutics, told NeurologyLive^®. "These data support the notion that we are acting throughout the cascade of events caused by dysfunctional, mutated GCase and prevent their occurrence. We were very pleased with the results as they add to the body of data that we have collected suggesting that GT-02287 corrects all components of the disease cascade."

In this study, presented by lead author Natalia Perez-Carmona, PhD, senior director of Biology at Gain Therapeutics, investigators aimed to understand the mechanism by which GT-02287 targets GCase and affects the underlying biological processes of PD. The study was conducted in collaboration with scientists in the group of Maurizio Molinari, PhD, professor at the Università dela Svizzera italiana-affiliated Institute for Research in Biomedicine in Bellinzona, Switzerland. The company applied its proprietary computational drug discovery platform to the recognition of the orally bioavailable and brain penetrant GT-02287. Investigators then had GCase function, ER stress, and protein quality control assessed in patient derived fibroblasts harboring mutated GCase. Additionally, researchers used a mutated GCase-HaloTag-HEK293 cell-based model to measure GCase transport to the lysosome.

"The results imply that, because we can affect each aspect of the disease cascade caused by misfolded GCase, for patients with GBA1-PD, or even patients not carrying a mutation in GBA1 (the gene that encodes GCase) but who also have dysfunctional GCase, as has been shown in cases of idiopathic PD, we can restore neuronal cell health and prevent neuronal cell death, holding out the promise of a disease modifying therapy," Taylor said. "The next stages of the research are to show that similar mechanisms occur in our animal models of the disease and in patients treated with the compound in clinical trials. We can do this by testing cells and body fluids derived from treated patients, compared with control groups. Confirmation of these mechanisms in patients will confirm the likelihood of our compound being a potential disease-modifying treatment for PD."

Further, in the results, investigators observed that GT-02287 mitigated UPR by reducing BiP levels and other selected UPR markers, inhibiting proteasomal degradation of L444P GCase. All told, this improvement instability facilitated GCase trafficking into lysosomes, where it could process its substrate efficiently for lysosomal and cellular health.

“These data further confirm our understanding of the mechanism of action of GT-02287, how it impacts cellular health by preventing the downstream consequences of GCase misfolding, including cellular stress and lysosomal dysfunction” Perez-Carmona said in a statement.¹ “The AD/PD conference is an important opportunity for us to continue to discuss our differentiated approach to addressing GBA1 PD through GCase modulation among this key audience.”

In early February 2024, the company announced preclinical data on GT-02287 presented at the 20th WORLDSymposium that demonstrated the agent’s ability to neuroprotect and restore motor function in PD models following delayed administration.² Findings showed that GT-02287 rescued cultured rat dopaminergic neurons injured with αSyn-PFFs, with or without the irreversible GCase inhibitorconduritol B epoxide, even when the compound was applied substantially later than the toxic insult. In the vivo mouse model, the agent also rescued locomotor impairment despite being administered several days after the initial toxic insult. Notably, motor rescue reflected in reduced levels of neurofilament light in plasma following the treatment of GT-02287.

“We believe the data showing complete restoration of motor function in a therapeutic model are remarkable and further support the potential of GT-02287 to slow or stop the progression of PD, a disease for which only symptomatic treatments are available to patients at this time,” Matthias Alder, chief executive officer, Gain Therapeutics, said in statement.² “We are currently conducting a phase 1 clinical trial of GT-02287 in healthy adults to evaluate its safety, tolerability, and pharmacokinetics, and plan to commence treatment of patients in an extension of that clinical trial in Q3 of this year.”