Repeat Expansions & Myotonic Dystrophy (REDs)
Our research focuses primarily on Myotonic Dystrophy, one of the most frequent neuromuscular diseases in adults. More specifically, our work is mainly concentrated on Myotonic Dystrophy type 1 (DM1), also known as Steinert disease. DM1 is characterised by progressive muscle weakness and atrophy, myotonia, heart conduction defects, cataracts, endocrine and gastrointestinal problems, as well as neurological manifestations. There are five clinical forms of this multisystemic disease, including late-onset, adult, juvenile, infantile and congenital forms. Currently, there is no treatment for this debilitating genetic disorder, but some therapeutic approaches are currently being developed.
DM1 is an autosomal dominant disease caused by the abnormal expansion of a CTG trinucleotide repeat (n>40) located in the 3′ non-coding region of the DMPK gene. The expanded CTG repeat sequence is highly unstable, further increasing in size not only in different tissues throughout the patient’s life, but also between successive generations. The expansion-biased intergenerational instability of the CTG repeat provides the molecular explanation for the anticipation phenomenon typical of this disease. DM1 is an RNA gain-of-function disease. Expanded DMPK transcripts containing pathological CUG repeats (RNA-CUGexp) are retained in the cell nucleus as riboprotein aggregates (foci) and disrupt the function of important RNA binding proteins (RBPs). In particular, RNA foci sequester RBPs of the MBNL family which are involved in RNA processing and maturation. Thus, the functional loss of MBNL activity leads to alternative splicing defects in a subset of RNA transcripts, which have been associated with key disease symptoms: the abnormal splicing of CLCN1 contributes to myotonia, INSR to insulin resistance, BIN1 to muscle weakness, DMD to altered muscle fibre architecture and SCN5A to defects in cardiac conduction and arrhythmias. However, additional mechanisms operating in various tissues and cell types are involved in the complex pathophysiology of this disease.
The REDs research team was created in 2019, following the merge of the teams of Geneviève Gourdon and Denis Furling. It also includes the group of Guillaume Bassez, a neurologist who coordinates the French Myotonic Dystrophy national registry (DM-Scope); and Arnaud Ferry’s group that focuses on muscle physiology and exercise. The aim of this new multidisciplinary team is to synergise efforts in order accelerate translational research for this neuromuscular disease, with the ultimate aim of offering novel and efficient therapeutic alternatives to patients. To this end, our team carries out integrated research on multiple aspects of DM1, from gene mutation to disease symptoms and the development of new therapeutic strategies. Our projects cover the fundamental mechanisms CTG repeat instability, the understanding of the pathophysiological mechanisms of disease using cellular and animal models, the development and assessment of innovative therapeutic approaches and, finally, the setting up of pre-clinical and clinical trials for DM1.
- Mechanisms of trinucleotide repeat instability in DM1 families, cell and mouse models.
- Molecular and pathophysiological consequences of CTG expansions in the central nervous system and in the congenital form of the disease.
- Preclinical therapeutic assays in DM1 mice, through the assessment of molecular and physiological phenotypes in muscle and CNS.
- Pathophysiological mechanisms triggered by the expression of CUGexp-RNA and the resulting changes in the motor unit and muscular function, as well as in other non-muscular manifestations (e.g. cardiovascular…).
- Development and evaluation of innovative therapeutic approaches for DM1 using cell and mouse models of the disease
- Impact of neuromuscular disease on muscle function and performance (i.e., characterisation of mouse models). Effects of exercise.
- Evaluation of therapeutic approaches on muscle function. Preclinical studies in mouse models, in collaboration with the UMS28 Phenotyping Platform (S. Morosan and M. Lemaitre).
- Integrated physiology of skeletal muscle.
- Phenotypic characterisation and natural history of Myotonic Dystrophy.
- Validation of measurement tools and readouts for clinical trials.
- Coordination of the French Observatory of Myotonic Dystrophies (DM-Scope).
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- Lo Scrudato, M, Poulard, K, Sourd, C, Tomé, S, Klein, AF, Corre, G et al.. Genome Editing of Expanded CTG Repeats within the Human DMPK Gene Reduces Nuclear RNA Foci in the Muscle of DM1 Mice. Mol Ther. 2019;27 (8):1372-1388. doi: 10.1016/j.ymthe.2019.05.021. PubMed PMID:31253581 PubMed Central PMC6697452.
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- Jauvin, D, Chrétien, J, Pandey, SK, Martineau, L, Revillod, L, Bassez, G et al.. Targeting DMPK with Antisense Oligonucleotide Improves Muscle Strength in Myotonic Dystrophy Type 1 Mice. Mol Ther Nucleic Acids. 2017;7 :465-474. doi: 10.1016/j.omtn.2017.05.007. PubMed PMID:28624222 PubMed Central PMC5453865.
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