I-Stem, Généthon and Kantify discover a promising therapy against genetic diseases

The teams of I-Stem and Généthon, laboratories of the French Association against Myopathies (AFM-Téléthon), collaborated with the Belgian start-up Kantify, specialized in the field of artificial intelligence, to demonstrate the efficacy, on cellular models, of a pharmacological combination for the treatment of alpha-sarcoglycanopathy, a neuromuscular disease. Published at the end of April in Frontiers in Pharmacology, this work, which combines high-throughput screening and artificial intelligence, opens up a new avenue for the treatment of this limb girdle muscular dystrophy which could prove encouraging for other genetic diseases, in particular cystic fibrosis..

Research partners

Created in 2005 by AFM-Téléthon, Inserm and the University of Evry, I-Stem is a research and development center dedicated to developing innovative treatments for genetic diseases using pluripotent stem cells ( ES and IPS). The institute uses these cells as tools to understand genetic diseases and identify or develop therapies (cell therapy, pharmacological screening).

Also created in 1990 by AFM-Téléthon, Généthon is a non-profit research and development center dedicated to gene therapy for rare diseases. Its objective: to clear the human genome, establish its first maps, track down the genes responsible for genetic diseases and use this knowledge to make innovative therapies.

Belgian start-up Kantify, which is on a mission to improve human health through AI, specializes in the development of AI solutions to accelerate drug discovery and automated diagnosis. At the beginning of 2022, the company announced its new Zeptomics AI-based solution, which is able to generalize, i.e. it can work on rare diseases or new molecules.

The research

Limb-girdle myopathies (or limb-girdle muscular dystrophies) manifest as progressive muscle weakness in the pelvis (pelvic girdle) and shoulders (scapular girdle) and affect 5 to 6 people out of 1 million. There are about thirty forms, one of them is linked to the deficiency of alphasarcoglycan (LGMD R3), a protein which stabilizes the membrane of the muscle cell during muscle contraction, it is one of the most common in Europe.

Work by Isabelle Richard, head of the “Progressive dystrophies” team at Généthon, had highlighted ” the molecular mechanisms involved in the most frequent forms of alpha-sarcoglycanopathy, in particular that caused by the R77C mutation (Human Molecular Genetics, May 2008)”. This mutation, present in a third of the patients concerned, leads to the production of a protein, alpha-sarcoglycan, which is malformed but can fulfill its function. ” Spotted by the biological mechanism ensuring the “quality control” of the proteins, it is destroyed, which then causes the disease. »

Successful collaboration thanks to AI

Based on Isabelle Richard’s research and on the identification of this mechanism, the “Pharmacology of muscular dystrophies” team of Xavier Nissan, at I-Stem, sought to identify drugs capable of preventing the degradation of this protein. The researchers first developed a cell model and then tested the effectiveness of nearly a thousand chemical molecules using high-throughput screening technology.

Once this screening was done, I-Stem and Kantify collaborated to identify the most interesting molecules. AI has made it possible to predict what could be the possible unforeseen effects in terms of toxicity of the affected compounds and to assess the potential success of their clinical development.

This work, carried out by Lucile Hoch, researcher at I-Stem, has thus shown that Givinostat, by inhibiting an enzyme (HDAC) which regulates the expression of a gene in the late phases of autophagy, a biological process during which malformed proteins are dissolved, coupled with Bortezomib, a drug that blocks another mechanism of protein destruction, the proteasome, was the most effective combination to prevent the degradation of the malformed R77C-alpha-sarcoglycan protein. This combination would prevent the onset of the disease.
Xavier Nissan says:

“Kantify’s AI technology allowed us to select the most promising candidate very quickly. We report in this study that the combination of Givinostat and Bortezomib preserves the most frequent forms of misfolded alpha sarcoglycan from degradation, but we have also shown that it has a positive impact on cystic fibrosis. It’s really exciting to see the power of this technology! »

Givinostat has indeed appeared as a potential therapy. To confirm this hypothesis, I-Stem and the teams from the Henri-Mondor hospital (Créteil) tested this molecule on cellular models of cystic fibrosis, a disease which mainly affects the respiratory tract, and were able to observe an amplification of effectiveness of treatments already used in the disease.

Xavier Nissan concludes:

“We are now working to validate this pharmacological approach in animal models with the aim of then launching a clinical trial. »

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I-Stem, Généthon and Kantify discover a promising therapy against genetic diseases


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