GT-02287 may slow Parkinson’s progression, new early data suggest
Treatment shown to boost motor function, coordination in mouse models: Gain
Gain Therapeutics has presented new preclinical data showing GT-02287, its experimental therapy for Parkinson’s disease, can slow disease progression in mouse and cellular models of the disease.
Overall, the treatment was shown to improve motor function and coordination, and activities of daily living in mouse models of Parkinson’s with and without GBA1 gene mutations. GT-02287 was also shown to reduce the levels of disease biomarkers, including alpha-synuclein clumping and plasma neurofilament light chain, a marker of neurodegeneration.
The data were presented at the Society for Neuroscience’s 2024 conference, held Oct. 5-9 in Chicago.
“The robust preclinical development dossier for GT-02287 presented further strengthen our belief that GT-02287 has the potential to be a disease-modifying therapy for people suffering from Parkinson’s disease,” Joanne Taylor, PhD, Gain’s senior vice president of research, said in a company press release. “The data demonstrate rescue of motor deficit and prevention of development of deficits in cognition which persisted even once the compound was removed.”
Genetic mutations in the GBA1 gene, which is responsible for producing the enzyme glucocerebrosidase (GCase), are the most prevalent genetic risk factor associated with Parkinson’s. GCase plays a role in breaking down and recycling fatty molecules within cells. When GBA1 mutations occur, the enzyme’s activity is impaired, leading to the buildup of harmful substances, such as misfolded proteins like alpha-synuclein and tau, which contribute to the development of Parkinson’s.
GT-02287 designed to prevent formation of toxic protein clumps in brain
GT-02287 is a small molecule that binds to GCase and restores its activity. This is expected to prevent the formation of toxic protein clumps in the brain, thereby slowing disease progression.
Recent data have shown GT-02287 was safe and well tolerated in a Phase 1 clinical trial in 73 healthy volunteers. Moreover, the treatment was found in the cerebrospinal fluid, the liquid which surrounds the brain and spinal cord, showing its ability to reach the brain.
At the conference, researchers presented preclinical data about GT-02287’s effects in animal and cellular models. In one scientific poster, titled “GT-02287, a clinical stage GCase regulator, demonstrates disease modifying capacity in both GBA1 and idiopathic Parkinson’s disease models, both GBA1 and idiopathic (meaning of unknown cause) mouse models of Parkinson’s were treated with GT-02287 orally, once daily, at 60 or 90 mg/kg doses.
Treatment not only improved motor function and coordination in both models, but it also prevented the development of deficits in cognition and activities of daily living. These positive effects were dose-dependent and maintained even after mice stopped receiving GT-02287.
“The preservation of motor and cognitive improvement in animal models of Parkinson’s disease associated with GT-02287 after its discontinuation coupled with the neuroprotective effects after delayed administration support the potential of GT-02287 to slow or stop the progression of Parkinson’s disease,” said Gene Mack, Gain’s interim CEO and chief financial officer.
In another poster, titled “GT-02287, a clinical stage GCase regulator, improves mitochondrial function and provides a neuroprotective effect in GBA1-Parkinson’s disease models,” the company presented data showing GT-02287 reduced the dysfunction of mitochondria in a cell and mouse model of GBA1-Parkinson’s. Mitochondria serve as the primary energy generators within cells, and as such, their proper function is necessary for maintaining cellular health. Impaired GCase activity leads to mitochondrial damage and subsequent dysfunction.
Treatment with GT-02287 also improved the function of lysosomes, or the cellular recycling centers whose dysfunction has been implicated in Parkinson’s; reduced alpha-synuclein clumping; and increased nerve cell survival. In the mouse model of GBA1-Parkinson’s, the treatment was also shown to reduce the blood levels of neurofilament light chain.
In another presentation, researchers also showed GT-02287 reduced tau accumulation in a human-derived cellular model engineered to express mutated tau protein that is more prone to clumping. According to Taylor, this also “demonstrates its potential to be a treatment for Alzheimer’s disease and other tauopathies.”
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