CC-03
Toxic RNA and myotonic dystrophy: from the dissection of disease mechanisms to the development of novel therapeutic strategies
Mário Gomes-Pereira, PhDI
IInserm, Imagine Institute for Genetic Diseases, Paris Descartes University, Sorbonne Paris - Cité University Paris, France
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Myotonic dystrophy (DM) is an autosomal dominant disorder, caused by the abnormal expansion of non-coding DNA repeats. The disease is highly multisystemic: in addition to the traditional muscle and cardiac symptoms, the neurological manifestations are particularly debilitating, affecting the daily life of patients and their families.
Transgenic mouse models of the disease have helped elucidate the molecular mechanisms of disease. Today we know that repeat-containing expanded RNA accumulates in the cell nucleus and impairs the activity of RNA-binding proteins, affecting primarily the regulation of alternative splicing in multiple tissues. DM is therefore the prototype of toxic RNA- mediated spliceopathy. Despite progress in the understanding of the molecular pathogenesis in skeletal muscle and heart, the disease pathways in the central nervous system remain unclear. In the laboratory we have generated a transgenic mouse model of DM carrying a large repeat expansion. DM mice recreate molecular features of RNA toxicity in the brain, associated with relevant behavioural and electrophysiological phenotypes. We have been using these animals to study the cell populations, neuronal circuits and molecular pathways primarily affected by the disease mutation in the central nervous system.
The remarkable progress in the dissection of disease pathobiology opened new avenues to the rational design of molecular therapies. Strategies to destroy or neutralise toxic RNA repeats have successfully rescued the phenotype of DM mouse models, and are now in clinical trials. The research path from the identification of disease mutation to the development of promising therapies took less than 20 years, making of DM not only a paradigm of RNA toxicity, but also an example of step- by-step dissection of a complex disease mechanism towards rational therapy design.
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