Gain Therapeutics Announces Preclinical Data Showing Restoration Of Enzymatic Function With Novel Allosteric Regulators In GM1 Gangliosidosis Model

Author: Benzinga Newsdesk | December 01, 2023 09:03am

Compounds significantly restored β-Gal function and reduced intracellular toxic substrates in model of GM1 gangliosidosis

 

Results published in PLOS ONE in collaboration with Institute for Research in Biomedicine

BETHESDA, Md., Dec. 01, 2023 (GLOBE NEWSWIRE) -- Gain Therapeutics, Inc., (NASDAQ:GANX), a clinical-stage biotechnology company leading the discovery and development of the next generation of allosteric small molecule therapies, today announced the publication of preclinical data identifying a novel class of small molecule allosteric regulators that demonstrate therapeutic potential for galactosidase beta 1 (GLB1)-related lysosomal storage disorders (LSDs), including GM1 gangliosidosis. The study, "Validation of a highly sensitive HaloTag-based assay to evaluate the potency of a novel class of allosteric β-Galactosidase correctors," was published in PLOS ONE.

GM1-gangliosidosis is an inherited, progressive disorder characterized by the degeneration of brain and spinal cord cells, leading to muscle weakness, skeletal abnormalities, dystonia, and vision problems. Mutations in the GLB1 gene significantly reduce the activity and function of the lysosomal hydrolase enzyme β-galactosidase (β-Gal) due to protein misfolding.

Depending on the age of onset, which can occur during infancy and up into adulthood, life expectancy of patients can be significantly shortened. Additionally, there are no available disease-modifying treatments for GM1 gangliosidosis, with available therapies only focused on reducing symptoms and improving quality of life. To enhance patient outcomes, there is a significant need to bring safe and effective treatments into the clinic that can alter progression of the disorder.

"Lysosomal storage disorders are difficult to treat with traditional pharmacological interventions because most approaches cause an inhibitory effect on the lysosomal enzyme by acting on the active site. The small allosteric regulators that we are characterizing correct protein misfolding by binding the mutated proteins outside the active site, without interfering with enzymatic activity," said Maurizio Molinari, PhD, Protein Folding and Quality Control Group Leader, Institute for Research in Biomedicine in Switzerland and senior author on the paper. "This impressive data demonstrates the potential of allosteric modulators as a therapeutic option for hard-to-treat, genetic diseases where there are no effective approaches for disease modification."

In the PLOS ONE study, scientists from Gain used Gain's proprietary Site-directed Enzyme Enhancement Therapy (SEE-Tx) technology followed by molecular interaction and ligand binding studies to identify and characterize two structurally targeted allosteric regulators of β-Gal. A biochemical HaloTag cleavage assay was developed by the researchers from the Institute for Research in Biomedicine and utilized to measure lysosomal delivery capabilities of β-Gal. Results showed that the two compounds (GT-00513 and GT-00413) stabilized, enhanced and restored the key biological lysosomal transport functions of β-Gal and reduced the levels of the intracellular toxic substrate, GM1 ganglioside, in GM1 gangliosidosis patient-derived cells.

"Restoring the function of misfolded proteins is a therapeutic approach that is accessible only through allosteric small molecule regulators that can be efficiently discovered with our pioneering computational drug discovery platform," said Manolo Bellotto, Chief Strategy Officer and General Manager of Gain Therapeutics and co-author on the paper. "This approach has been validated with our clinical-stage lead drug candidate GT-02287, which restores the function of glucocerebrosidase for the treatment of Parkinson's disease and repairs the disease cascade triggered by protein misfolding."

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