Use of Human Pluripotent Stem Cells for Deciphering Myotonic Dystrophy Type 1

Presented on September 8th, 2023.

Cécile Martinat, PhD
I-Stem - Institut des cellules Souches pour le Traitement et l'Etude des maladies Monogéniques

Authors: Sandrine Baghdoyan, Azania Abatan, Noémie Berenger-Currias, Morgan Gazzola, Cécile Martinat

Understanding the mechanisms by which a genetic variation contributes to diseases is a central aim of human genetics and should greatly facilitate the development of preventive strategies and treatments. Implementing this approach to understand the cellular and molecular basis of neuromuscular disorders (NMDs) is particularly challenging due to the inherent inaccessibility of the affected cell types from patients. Despite the wealth of existing cellular and animal models, progresses towards identification of new treatments have been hampered by the incomplete understanding of the pathogenic mechanisms involved in these diseases as well as the availability of relevant screening tools. The development of convenient Human models that even more closely replicate the disease will undoubtedly improve pathological modeling of neuromuscular disorders as well as more adapted therapeutics. In this context, my group is interested in developing an in vitro human “toolbox” to establish pathological models of representative NMDs based on the use of human pluripotent stem cells. Validating this concept, we demonstrated that human pluripotent stem cells, expressing the causal mutation implicated in Myotonic Dystrophy type 1 (DM1), offer pertinent disease-cell models, applicable for a wide systemic analysis ranging from mechanistic studies to therapeutic screening. Thus, we identified developmental molecular defects involved in myogenesis as well as in neurite formation and establishment of neuromuscular connections. In parallel to these mechanistic studies, we are also interested in using these new disease-specific cell models to identify new therapeutic strategies.

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