Oral GT-02287 Shows Potential to Support Nerve Cell Health

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Treatment with GT-02287, an experimental oral therapy for Parkinson’s disease, corrected numerous damaging abnormalities associated with Parkinson’s in cell models, according to new data shared at a recent conference.

“The data we presented at the Synuclein Meeting demonstrates further encouraging disease modifying potential for patients with Parkinson’s disease who currently have no effective treatment options,” Eric Richman, CEO of Gain Therapeutics that is developing the therapy, said in a press release.

GT-02287 is designed to increase the activity of an enzyme called beta-glucocerebrosidase (GCase), which plays a critical role in the function of lysosomes. Known as the cell’s “recycling factories,” lysosomes are responsible for breaking down complex molecules into simple components that can be repurposed by cells.

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Low GCase activity is common in Parkinson’s and  thought to contribute to the toxic buildup of the alpha-synuclein protein that characterizes the disease. Mutations in the GBA1 gene that encodes the GCase enzyme, or protein, also are associated with a higher risk of Parkinson’s.

GT-02287 was designed using Gain’s Site-directed Enzyme Enhancement Therapy system, which analyzes the 3D structure of proteins to determine how they and potential therapies are likely to interact. By binding to GCase, GT-02287 was designed to increase the protein’s stability, helping it retain the proper shape it needs to work correctly.

The candidate treatment has also shown potential in animal models of Parkinson’s.

“Our lead candidate … can allosterically bind and stabilize GCase, thus avoiding its degradation and allowing its transport to the lysosomes where the enzyme can carry out its biological function,” said Manolo Bellotto, PhD, president and general manager of Gain.

The new work, presented in the poster Targeting Glucocerebrosidase with Structurally Targeted Allosteric Regulators Corrects Abnormal Phenotypes in Models of Parkinson’s Disease,” involved experiments testing GT-02287 in a human nerve cell line called BE2-M17, and in a model of rat neurons. Both models included types of nerve cells of relevance to Parkinson’s: wild-type dopaminergic neurons — those without mutations — and neurons harboring two disease-associated mutations in the GBA1 gene, L444P and N370S, Gain reported.

Treatment with GT-02287 was seen to increase the activity of GCase, improve the health of lysosomes, and lower the accumulation of alpha-synuclein in the cells. The treatment also aided neuronal survival and connections between different nerve cells.

“Interestingly, there appears to be an inverse relationship between GCase and α-syn [alpha-synuclein] levels: reduced GCase function is associated with increased α-syn accumulation as well as a change from its soluble form to its aggregated form,” the researchers wrote.

“GT-02287 restores GCase-related key biological activities found to be impaired in many forms of [Parkinson’s disease], thus warranting further development towards the clinic,” they added. “Restoring dysfunctional GCase may … represent a potential therapeutic strategy.”

“The new data builds on a body of evidence showing a beneficial effect of our lead candidate on enzyme levels, substrate depletion, lysosomal health, and most importantly for disease pathology, neuronal health,” Bellotto said.