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Identification of CTG.CAG contraction factors in Myotonic Dystrophy type 1

Abstract

Objectifs Myotonic dystrophy type 1 (DM1) is a neuromuscular disease caused by an unstable CTG repeat expansion in the DMPK gene. Larger expansions are associated with more severe symptoms and a decreasing age of onset. We hypothesize that the development of innovative therapeutic strategies, aimed at decreasing the CTG repeat length, and thus to stop or reverse the progression of the disease, may improve the quality of life of patients. The specific objective of our work is to uncover bioactive molecules able to induce repeat contractions in trinucleotide repeat (TNR) models and to decipher the mechanisms promoting these contractions using efficient tools. Contenu We performed a large-scale screen for pharmacologically relevant chemical modulators of instability using the Prestwick Library taking advantage of a chromosomal GFP reporter that can accurately measure CTG repeat changes in a HEK293 cell population. The effect of selected molecules directly on the dynamics of CTG repeat instability is studied in HEK293 cells as well as DM1 fibroblasts using targeted long-read sequencing. During the chemical screen, we identified candidate molecules notably involved in epigenetic regulation pathways, that may modulate the size of CTG repeats. Some of these molecules induced stabilization or even contractions of CTG repeats in the HEK cell model and in DM1 fibroblasts. The direct perspective of our work is to identify new small molecules and new druggable targets promoting CAG.CTG repeat contractions, thus offering new therapeutic perspectives for DM1 and TNR diseases.
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Dates and versions

hal-04004435 , version 1 (24-02-2023)

Identifiers

  • HAL Id : hal-04004435 , version 1

Cite

Laure de Pontual, Guillaume Diop, Sonia Lameiras, Tina Alaeitabar, Sylvain Baulande, et al.. Identification of CTG.CAG contraction factors in Myotonic Dystrophy type 1. 19ème Journées de la Société Française de Myologie (JSFM), Nov 2022, Toulouse, France. ⟨hal-04004435⟩
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