Teams from I-Stem and Genethon, laboratories of the Association Française contre les Myopathies (AFM-Telethon), have collaborated with the Belgian start-up Kantify, which specializes in the field of artificial intelligence, to demonstrate the efficacy of a pharmacological combination for the treatment of alpha-sarcoglycanopathy, a neuromuscular disease, in cellular models. 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 myopathy that could prove encouraging for other genetic diseases, notably cystic fibrosis.

Research partners

Created in 2005 by the AFM-Telethon, Inserm and the University of Evry, I-Stem is a research and development center dedicated to the development of 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 the AFM-Telethon, Genethon 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 develop innovative therapies.

Belgian startup Kantify, whose mission is 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 AI-based solution Zeptomics, which is capable of generalization, meaning it can work on rare diseases or new molecules.

The research

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

The work of Isabelle Richard, head of the “Progressive Dystrophies” team at Genethon, 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 poorly formed but can fulfil its function. ” When detected by the biological mechanism that ensures the “quality control” of proteins, it is destroyed, which then causes the disease.

Successful collaboration using AI

Based on Isabelle Richard’s research and the identification of this mechanism, Xavier Nissan’s “Pharmacology of Muscular Dystrophies” team at I-Stem sought to identify drugs capable of preventing the degradation of this protein. The researchers first developed a cellular model and then tested the effectiveness of nearly 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. AI was used to predict what the potential unforeseen toxicity effects of the affected compounds might be and to assess the potential success of their clinical development.

This work, carried out by Lucile Hoch, a researcher at I-Stem, showed that Givinostat, by inhibiting an enzyme (HDAC) that regulates the expression of a gene in the late phases of autophagy, the biological process during which malformed proteins are dissolved, coupled with Bortezomib, a drug that blocks another protein destruction mechanism, 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 states:

“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 not only preserves the most common 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 emerged as a potential therapeutic. To confirm this hypothesis, I-Stem and teams from the Henri-Mondor Hospital (Créteil) tested this molecule on cell models of cystic fibrosis, a disease that mainly affects the respiratory tract, and were able to observe an amplification of the efficacy of treatments already used in the disease.

Xavier Nissan concludes:

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

Translated from I-Stem, Généthon et Kantify découvrent une thérapie prometteuse contre les maladies génétiques