GT-02287 aids motor, cognitive function in GBA1 Parkinson’s mice
Data come as Phase 1 clinical trial evaluates safety profile
Once-daily treatment with Gain Therapeutics‘ GT-02287 rescued motor function and cognitive performance in a mouse model of Parkinson’s disease associated with mutations in the GBA1 gene.
“These data further confirm our conviction that GT-02287 can slow or stop progression of Parkinson’s disease and given the cognitive decline observed in GBA1 Parkinson’s patients, we hope that we can one day deliver this drug to those that need it and help them improve their everyday life,” Joanne Taylor, PhD, Gain’s senior vice president of research, said in a company press release.
GT-02287’s safety profile is being investigated in a two-part, Phase 1 clinical trial involving healthy volunteers in Australia. In the first part, which began last year, participants received single doses of the therapy. Following a safety committee review of the data, participants began receiving multiple ascending doses in March.
New preclinical data were presented as a poster at the Federation of European Neuroscience Societies (FENS) Forum 2024 in Austria.
“FENS Forum 2024 is an important opportunity for us to continue discussing our differentiated approach to addressing GBA1 Parkinson’s disease and further discourse and collaboration with the neuroscience community,” Taylor said.
Improving nerve cells
GBA1 gene mutations are a common genetic cause of Parkinson’s. This gene provides instructions for an enzyme called glucocerebrosidase, or GCase, which helps degrade the glucocerebroside molecule inside lysosomes, the cell’s recycling centers.
When GBA1 is mutated, the enzyme is less active, disrupting lysosomal function. Without proper recycling functions, proteins like alpha-synuclein can build up and form toxic clumps, which is a hallmark of Parkinson’s.
GT-02287 is a small-molecule allosteric enzyme activator, meaning it binds to GCase and restores its activity. It’s intended to improve lysosome function so that alpha-synuclein can be prevented from forming these toxic clumps in nerve cells in the brain.
In previous preclinical studies, GT-02287 improved nerve cell health and fine motor skills in mice and reduced the blood levels of the neurofilament light chain (NfL), indicating less nerve cell damage. GT-02287 also protected dopamine-producing nerve cells, which are damaged in Parkinson’s, from the toxic insult by alpha-synuclein clumping, while restoring lysosome function.
The poster presented new data on GT-02287’s impact on nest-building behavior in a Parkinson’s mouse model. Nest-building is a spontaneous mouse behavior that reflects cognitive performance and daily living tasks in humans.
Researchers injected alpha-synuclein fibrils into mouse brains with a GCase inhibitor for 28 days as a model for GBA1-associated Parkinson’s. GT-02287 was given orally once daily at three increasing doses (30, 60, and 90 mg/kg), starting eight days after the initial toxic insult. Nest-building was assessed by scoring the quality of the nest.
Nest-building was markedly compromised in GBA1-Parkinson’s mice compared with healthy controls. In comparison, treatment with GT-02287 improved nest-building performance in a dose-dependent manner, particularly at the two higher doses, which showed statistically significant improvements compared with untreated Parkinson’s mice.
Using the wire hang tests for motor function, GBA1-Parkinson’s mice treated with GT-02287 held onto the elevated wire frame significantly longer at all doses than untreated mice, also in a dose-dependent manner.
Nest-building and motor function improvements correlated with dose-dependent reductions in various Parkinson’s-related biomarkers, including brain-aggregated alpha-synuclein, blood NfL and Iba-1 and GFAP, two markers of brain inflammation.
A second group of mice received the fibrils only as a model of idiopathic Parkinson’s, with an unknown cause. These mice received a similar treatment regimen with a single dose of GT-02287 (90 mg/kg).
These mice experienced similar GT-02287-related improvements in motor function and biomarker levels of aggregated alpha-synuclein, Iba-1, and GFAP.
However, untreated idiopathic Parkinson’s mice showed no deficits in nest-building or increases in blood NfL levels, suggesting that “deficits in complex behaviour, which are correlated with increased plasma NfL levels, take longer to develop than deficits in motor behaviour in the absence of lowering of GCase activity,” the researchers wrote.
The treatment “can rescue deficits in complex behaviours in which cognitive function is involved in a GBA1-[Parkinson’s disease] model in addition to improving motor function deficits in this model,” they wrote.
Gain’s development program for GT-02287 is supported by The Michael J. Fox Foundation for Parkinson’s Research, The Silverstein Foundation for Parkinson’s with GBA, Eurostars-2 joint program, and by cofunding from the European Union Horizon 2020 research and Innosuisse.
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