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STAR candidates for the treatment of Gaucher Disease enhance GCase activity in a neuronal cell model and reduce toxic accumulation of GCase substrate

STAR candidates for the treatment of GM1 gangliosidosis and Morquio B increase β-gal maturation and delivery to the lysosome and enhance β-gal activity in a panel of fibroblast cell lines

BETHESDA, Md., Feb. 11, 2021 (GLOBE NEWSWIRE) -- Gain Therapeutics, Inc., (“Gain”) a biotechnology company focused on redefining drug discovery by identifying and optimizing allosteric binding sites that have never before been targeted, today announced new pre-clinical data from its Gaucher disease, GM1 gangliosidosis and Morquio B programs. The findings will be highlighted in three e-poster presentations at the 17th annual WORLDSymposium™, a research conference dedicated to lysosomal diseases.

“We continue to see evidence that structurally targeted allosteric regulators (STARs) have the ability to increase enzymatic activity in proteins whose deficiency can lead to devastating diseases such as Gaucher disease and GLB1-related disorders,” said Dr. Manolo Bellotto, General Manager and President at Gain. “Data from these three studies presented at the WORLDSymposium™ showcase the ability of STARs to successfully target regulatory allosteric sites in in vitro models leading to depletion of the toxic substrate. These data provide clear evidence that orally bioavailable STARs can penetrate hard-to-treat tissues and reduce substrate accumulation, the root cause of these diseases.”

Eric I. Richman, Chief Executive Officer, added, “We are encouraged by the data presented at the WORLDSymposium™ demonstrating the potential of Gain’s Site-directed Enzyme Enhancement Therapy (See-Tx™) proprietary computational platform to identify lead STAR compounds for potential treatment of rare genetic and neurodegenerative diseases. With these positive and encouraging data, we will continue to move the programs forward and look forward to additional studies to develop treatments for patients in need.”

Key findings and details for each presentation are highlighted below.

Insights into the mechanism of action of structurally targeted allosteric regulators for the treatment of Gaucher disease
The mechanism of action of lead STAR compounds being developed for the treatment of Gaucher disease (GD), a lysosomal storage disorder characterized by a deficiency in Glucocerebrosidase (GCase), was assessed. STARs were evaluated in a number of assays to understand their binding and stabilization of GCase and enhancement of the enzyme. Lysosomal GCase levels following treatment with STARs in wildtype and patient-derived fibroblasts were also measured. Key conclusions from the presentation include:

  • GCase STARs identified via Gain’s proprietary See-Tx platform effectively bind GCase, as measured by direct binding studies performed by Surface Plasmon Resonance (SPR)
  • GCase STARs stabilize GCase in a dose-dependant manner, as evaluated by a thermal shift assay with GCase in the presence and absence of STARs
  • GCase STARs do not inhibit GCase activity when administered to wildtype fibroblasts
  • Treatment with GCase STARs leads to an increase in lysosomal GCase
  • STARs enhance GCase activity in wildtype and a panel of Gaucher patient-derived fibroblasts bearing prevalent mutations
Presentation Details:
Title: Insights into the mechanism of action of structurally targeted allosteric regulators for the treatment of Gaucher disease
Presenter: Natàlia Pérez Carmona, Ph.D., Gain Therapeutics
Date/Time: February 12, 2021 at 2:30 p.m. EST

Preclinical development of brain-penetrant structurally targeted allosteric regulators for the treatment of neuronopathic Gaucher disease
GCase activity was measured in several cell types – human fibroblasts, mouse fibroblasts and dopaminergic-like neuronal cells to determine the ability of STARs to stabilize mutant GCase in a non-inhibitory manner and support proper folding. Key conclusions from the presentation include:

  • GCase STARs enhance GCase activity across both wildtype and a series of Gaucher patient-derived fibroblasts
  • Treatment with GCase STARs is associated in a significant reduction of toxic GCase substrate accumulated in neuropathic L444P fibroblasts
  • STARs enhance GCase activity in a dopaminergic-like neuronal cell model
  • STARs are brain penetrant and orally bioavailable
Presentation Details:
Title: Preclinical development of brain-penetrant structurally targeted allosteric regulators for the treatment of neuronopathic Gaucher disease
Presenter:Ana Maria García-Collazo, Ph.D., Gain Therapeutics
Date/Time: February 12, 2021 at 2:30 p.m. EST

Insights into the mechanism of action of structurally targeted allosteric regulators for the treatment of GLB1-related disorders
The mechanism of action of lead STAR compounds, being developed for the treatment of GLB1-related disorders, such as GM1 gangliosidosis and Morquio B syndrome was assessed. GM1 gangliosidosis and Morquio B are both characterized by a deficience of β-galactosidase (β-gal). STARs were evaluated to understand their affinity and effects on β-gal. Additionally, β-gal maturation, delivery to the lysosome and activity were measured. Key conclusions from the presentation include:

  • β-gal STARs identified via Gain’s proprietary See-Tx platform effectively bind β-gal
  • β-gal STARs do not inhibit GCase activity when administered to wildtype fibroblasts
    • Bind to the target enzyme in a non-inhibitory manner
  • β-gal STARs increase β-gal maturation and delivery to the lysosome, presumably by rescuing it from early degradation in the endoplasmic reticulum
  • β-gal STARs enhance both enzymatic activity in a panel of fibroblast cell lines
  • β-gal STARs decrease substrate accumulation in canine fibroblasts
Presentation Details:
Title: Insights into the mechanism of action of structurally targeted allosteric regulators for the treatment of GLB1-related disorders
Presenter:Tiziana Rosa, Pharm.D., Ph.D., Gain Therapeutics
Date/Time:February 12, 2021 at 2:30 p.m. EST

About Gain Therapeutics, Inc.
Gain Therapeutics, Inc. is redefining drug discovery with its See-Tx™ target identification platform. By identifying and optimizing allosteric binding sites that have never before been targeted, Gain is unlocking new treatment options for difficult-to-treat disorders characterized by protein misfolding. Gain was originally established in 2017 with the support of its founders and institutional investors such as TiVenture, 3G Future Health Fund (formerly known as Helsinn Investment Fund) and VitaTech. It has been awarded funding support from The Michael J. Fox Foundation for Parkinson’s Research (MJFF) and The Silverstein Foundation for Parkinson’s with GBA, as well as from the Eurostars-2 joint program with co-funding from the European Union Horizon 2020 research and Innosuisse. In July 2020, Gain Therapeutics, Inc. completed a share exchange with GT Gain Therapeutics SA., a Swiss corporation, whereby GT Gain Therapeutics SA became a wholly owned subsidiary of Gain Therapeutics, Inc.

For more information, visit https://www.gaintherapeutics.com/

Forward-Looking Statements
Any statements in this release that are not historical facts may be considered to be “forward-looking statements.” Forward-looking statements are based on management’s current expectations and are subject to risks and uncertainties which may cause results to differ materially and adversely from the statements contained herein. Such statements include, but are not limited to, statements regarding the market opportunity for product candidates of Gain Therapeutics, Inc. (Gain) and the business strategies and development plans of Gain. Some of the potential risks and uncertainties that could cause actual results to differ from those predicted include Gain’s ability to: make commercially available its products and technologies in a timely manner or at all; enter into other strategic alliances, including arrangements for the development and distribution of its products; obtain intellectual property protection for its assets; accurately estimate its expenses and cash burn and raise additional funds when necessary. Undue reliance should not be placed on forward-looking statements, which speak only as of the date they are made. Except as required by law, Gain does not undertake any obligation to update any forward-looking statements to reflect new information, events or circumstances after the date they are made, or to reflect the occurrence of unanticipated events.

Investor Contact:
Daniel Ferry
LifeSci Advisors
+1 617-430-7576
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Media Contact:
Cait Williamson, Ph.D.
LifeSci Communications
+1 646-751-4366
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