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

The team of I-Stem and Généthon, a laboratory of the French Association, collaborated with Myopathies (AFM-Téléthon), Belgian start-up Cantify, to demonstrate effectiveness in cellular models, specialized in artificial intelligence. Alpha-sarcoglycanopathy, a pharmacological combination for the treatment of neuromuscular disease. Published in late April in Frontiers in Pharmacology, the work, which combines high-throughput screening and artificial intelligence, opens up a new avenue for the treatment of muscular dystrophy in these organs that may prove promising for other genetic diseases, especially cystic fibrosis..

Research partner

Created in 2005 by AFM-Téléthon, Inserm and Evry University, 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 for understanding genetic diseases and for identifying or developing therapies (cell therapy, pharmacological screening).

Also created by AFM-Téléthon in 1990, Généthon is a non-profit research and development center dedicated to gene therapy for rare diseases. Its purpose is to clean the human genome, to establish its first map, to trace the genes responsible for genetic diseases, and to use this knowledge to create innovative therapies.

Belgian start-up Cantify, which is on a mission to improve human health through AI, specializes in developing AI solutions to accelerate drug discovery and automated diagnosis. In early 2022, the company announced its new Zeptomic AI-based solution, capable of generalizing, meaning it could work on rare diseases or new molecules.


Lumbar girdle myopathy (or limb girdle muscular dystrophy) manifests as progressive muscle weakness in the pelvis (pelvic girdle) and shoulder (scapular girdle) and affects 5 to 6 people in 1 million. There are about thirty forms, one of which is associated with a deficiency of alphasarcoglycan (LGMD R3), a protein that stabilizes muscle cell membranes during muscle contraction, one of the most common in Europe.

Highlights the work of Isabel Richard, head of Généthon’s “Progressive Dystrophy” group. ” Molecular processes involved in the most frequent forms of alpha-sarcoglycanopathy, especially those caused by R77C mutations (Human Molecular Genetics, May 2008) “. This mutation, present in one-third of the patients concerned, leads to the production of a protein, alpha-sarcoglycan, which is deformed but can perform its function. ” Characterized by the biological process of ensuring the “quality control” of proteins, it is destroyed, which later causes disease. A

Thanks to AI for successful collaboration

Based on Isabel Richard’s research and the identification of this process, Xavier Nissan’s “Pharmacology of Muscular Dystrophies” team at I-STEM tried to identify drugs capable of inhibiting this protein degradation. The researchers first created a cell model and then tested the effectiveness of about a thousand chemical molecules using high-throughput screening technology.

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

The work, led by i-stem researcher Lucille Hoch, showed that givinostat, an enzyme (HDAC) inhibitor that regulates the expression of a gene in the late stages of autophagy, is a biological process that degrades proteins. Dissolved, combined with bortezomib, a drug that blocks another process of protein destruction, was the most effective combination to prevent the degradation of proteasome, a distorted R77C-alpha-sarcoglycan protein. This combination will prevent the onset of the disease.
Xavier Nissan says:

“Kantify’s AI technology allows us to select the most promising candidates very quickly. We have reported in this study that a combination of Givinostat and Bortezomib most frequently protects the misfolded alpha sarcoglycan from degradation, but we have also shown that it has a positive effect on cystic fibrosis. Really exciting to see the power of this technology! A

Givinostat has actually emerged as a potential therapy. To confirm this hypothesis, teams from i-Stem and Henry-Monder Hospital (Cretil) tested the molecule on cellular models of cystic fibrosis, a disease that mainly affects the respiratory tract, and was able to observe an increase in treatment efficacy. Already used in diseases.

Xavier Nissan concludes:

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

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