Gain Therapeutics Announces Preclinical Data Showing Restoration of Enzymatic Function with Novel Allosteric Regulators in GM1 Gangliosidosis Model

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
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
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
correctors,” was published in PLOS ONE.
is an inherited, progressive disorder characterized by the degeneration of brain and spinal cord cells, leading to
muscle weakness
, skeletal abnormalities,
, 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
for the treatment of
Parkinson’s disease
and repairs the disease cascade triggered by protein misfolding.”

About Gain Therapeutics, Inc.

Gain Therapeutics, Inc. is a clinical-stage biotechnology company leading the discovery and development of next generation allosteric therapies. Gain’s lead drug candidate GT-02287, in development for the treatment of GBA1 Parkinson’s disease, is currently being evaluated in a Phase 1 clinical trial.
Leveraging AI-supported structural biology, proprietary algorithms and supercomputer-powered physics-based models, the company’s SEE-Tx® discovery platform can identify novel allosteric binding sites on disease-implicated proteins, pinpointing pockets that cannot be found or drugged with current technologies. Gain’s unique approach enables the discovery of novel, allosteric small molecule modulators that can restore or disrupt protein function. Deploying its highly advanced platform, Gain is accelerating drug discovery and unlocking novel disease-modifying treatments for untreatable or difficult-to-treat disorders including
neurodegenerative diseases
rare genetic disorders
and oncology. For more information, please visit and follow us on LinkedIn.

About Institute for Research in Biomedicine (IRB, Bellinzona), an institute affiliated to Università della Svizzera italiana (USI)

Founded in 2000 in Bellinzona, Switzerland, the Institute for Research in Biomedicine (IRB) hosts 13 research groups studying infectious, inflammatory, tumors and rare diseases in order to identify new therapeutic strategies. As a result of its activities, the IRB has gained considerable international recognition in the fields of immunology, cell and structural biology and DNA repair. Molinari’s laboratory investigates the molecular mechanisms regulating chaperone-assisted protein folding and the quality control processes determining whether a polypeptide should be transported at the intra- or extra-cellular site of activity, or if it should be selected for degradation. Emphasis is given on establishing causes of diseases resulting from misfolding of mutant gene products such as
deficiency and lysosomal storage disorders and to explore novel therapeutic approaches to alleviate disease phenotypes. IRB offers training opportunities for young researchers at all levels. This is made possible through collaborations with Swiss and foreign universities. Since its opening, IRB has trained more than 1210 PhD students who have gone on to careers in academia or industry both in Switzerland and abroad. In 2021, IRB and IOR (Institute of Oncology Research) formed the Bios+ (Bellinzona Institutes of Science) association, with the mission to create new synergies and to promote and coordinate the scientific research and teaching activities of the two institutes. The vision of Bios+ is to promote the growth of a biomedical research center in Italian-speaking Switzerland. For more information, please visit

About the research group of Prof. Molinari (IRB, Bellinzona)

The Protein Folding and Quality Control group lead by Prof. Molinari was established at the IRB in 2000. The group is dissecting the mechanisms that regulate the chaperone-assisted production of correctly folded proteins in the Endoplasmic Reticulum (ER), and the quality control events that select misfolded proteins for proteasome-driven ER-Associated Degradation (ERAD), or for lysosome-driven ER-to-Lysosome-Associated Degradation (ERLAD). Studies are ongoing to characterize the unfolded protein responses (UPR) and the ER-phagy pathways that operate in mammalian cells to ensure the adaptation of ER size and activity to the cellular needs.
A thorough knowledge of the processes that maintain ER function is instrumental to identify drug targets and to design and assess therapies for human diseases elicited by pathogens or linked to aberrant ER homeostasis resulting from expression of defective gene products (e.g., rare genetic disorders such as alpha1-antitrypsin deficiency or lysosomal storage disorders). For more information, please visit Lab Molinari, X and LinkedIn.
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