Pluripotent Stem Cells in Disease Modeling and Drug Discovery for Myotonic Dystrophy Type 1

Abstract

Myotonic dystrophy type 1 (DM1) is a progressive multisystemic disease caused by the expansion of a CTG repeat tract within the 3′ untranslated region (3′ UTR) of the dystrophia myotonica protein kinase gene (DMPK). Although DM1 is considered to be the most frequent myopathy of genetic origin in adults, DM1 patients exhibit a vast diversity of symptoms, affecting many different organs. Up until now, different in vitro models from patients’ derived cells have largely contributed to the current understanding of DM1. Most of those studies have focused on muscle physiopathology. However, regarding the multisystemic aspect of DM1, there is still a crucial need for relevant cellular models to cover the whole complexity of the disease and open up options for new therapeutic approaches. This review discusses how human pluripotent stem cell–based models significantly contributed to DM1 mechanism decoding, and how they provided new therapeutic strategies that led to actual phase III clinical trials.

Curriculum vitae of CUG binding protein 1 (CELF1) in homeostasis and diseases: a systematic review

“…Myotonic dystrophy is an autosomal dominant genetic disorder that impacts various organ systems, encompassing the skeletal muscles, heart, and brain [ 28 – 31 ]. Specifically, DM1 arises from an aberrant expansion of microsatellite DNA, leading to the sequestration of non-coding RNA products by RNA splicing factors [ 32 , 33 ]. This sequestration event results in the loss of functionality of RNA splicing factors, leading to widespread abnormalities in selective RNA splicing.…”