The focus of our activities is to develop therapeutic strategies for muscular dystrophies (MD). MDs are debilitating diseases affecting the skeletal muscle. Muscle involvement is associated with elevated levels of serum creatine kinase and is marked by a dystrophic profile including areas of degeneration / regeneration, variable fiber size, and inflammatory infiltrates. There is no curative treatment for muscular dystrophies apart from supportive care. There is therefore an important medical need since these diseases are associated with morbidity due to cardiac and respiratory failures and with an important reduction of the quality of life. Indeed, daily activities are progressively hampered by the loss of muscle mass and force.


MD can be caused by genetic defects in more than 40 different genes. Our team made the strategic choice to focus on the most frequent forms of the disease, which include the relatively frequent Duchenne muscular dystrophy (DMD) and the genetically heterogeneous group of limb-girdle muscular dystrophies (LGMD). A particular subset of LGMD is caused by mutations in genes encoding constituents of the dystrophin-associated glycoprotein complex [DGC]. One role of the DGC is to maintain the sarcolemma stability by providing a physical link between the extracellular matrix (ECM) and the actin cytoskeleton and protecting the muscle cells from contraction-induced damages. Another subset of LGMD is due to the deficiency of various enzymes involved in glycosylation pathways, this post-translational modification of proteins being important for the anchoring of the muscle cells to the ECM. Two of the LGMDs are caused by mutations in members of the membrane repair machinery (dysferlin and anoctamin5). Others are caused by defects in sarcomeric proteins or enzymes (titin and calpain 3), although the mechanism leading to muscle degeneration remains to be determined.


To reach our goal of finding a cure for these diseases, we are developing several axes of research including investigation of pathophysiological mechanism of the diseases, evaluation of approaches based on the in vivo delivery of adeno-associated viral (AAV) vectors or on gene editing, identification of potential diagnostic and prognostic biomarkers and participation in genetic or clinical evaluation of patients. Following establishment of proof-of-principle, several of the approaches we developed are now being translated to the clinics.




William Lostal, Carinne Roudaut, Marine Faivre, Karine Charton, Laurence Suel, Nathalie Bourg, Heather Best, John Edward Smith, Jochen Gohlke, Guillaume Corre, Xidan Li, Zaher Elbek, Ralph Knoell, Jack-Yves Deschamps, Henk Granzier, and Isabelle Richard. Titin splicing regulates cardiotoxicity associated with calpain 3 gene therapy for limb-girdle muscular dystrophy type 2a. Science Translational Medicine, 11(520), 2019. [ DOI | arXiv | full text| abstract]


S. F. Henriques, E. Gicquel, J. Marsolier, and I. Richard. Functional and cellular localization diversity associated with Fukutin-related protein patient genetic variants. Hum. Mutat., 40(10):1874-1885, 10 2019. [DOI:10.1002/humu.23827] [PubMed:31268217].


D. Israeli, J. Cosette, G. Corre, F. Amor, J. Poupiot, D. Stockholm, M. Montus, B. Gjata, and I. Richard. An AAV-SGCG Dose-Response Study in a γ-Sarcoglycanopathy Mouse Model in the Context of Mechanical Stress. Mol Ther Methods Clin Dev, 13:494-502, Jun 2019. [PubMed Central:PMC6545357] [DOI:10.1016/j.omtm.2019.04.007] [PubMed:31194043].


E. C. Oates, K. J. Jones, S. Donkervoort, A. Charlton, S. Brammah, J. E. Smith, J. S. Ware, K. S. Yau, L. C. Swanson, N. Whiffin, A. J. Peduto, A. Bournazos, L. B. Waddell, M. A. Farrar, H. A. Sampaio, H. L. Teoh, P. J. Lamont, D. Mowat, R. B. Fitzsimons, A. J. Corbett, M. M. Ryan, G. L. O'Grady, S. A. Sandaradura, R. Ghaoui, H. Joshi, J. L. Marshall, M. A. Nolan, S. Kaur, J. Punetha, A. Topf, E. Harris, M. Bakshi, C. A. Genetti, M. Marttila, U. Werlauff, N. Streichenberger, A. Pestronk, I. Mazanti, J. R. Pinner, C. Vuillerot, C. Grosmann, A. Camacho, P. Mohassel, M. E. Leach, A. R. Foley, D. Bharucha-Goebel, J. Collins, A. M. Connolly, H. R. Gilbreath, S. T. Iannaccone, D. Castro, B. B. Cummings, R. I. Webster, L. Lazaro, J. Vissing, S. Coppens, N. Deconinck, H. M. Luk, N. H. Thomas, N. C. Foulds, M. A. Illingworth, S. Ellard, C. A. McLean, R. Phadke, G. Ravenscroft, N. Witting, P. Hackman, I. Richard, S. T. Cooper, E. J. Kamsteeg, E. P. Hoffman, K. Bushby, V. Straub, B. Udd, A. Ferreiro, K. N. North, N. F. Clarke, M. Lek, A. H. Beggs, C. G. Bonnemann, D. G. MacArthur, H. Granzier, M. R. Davis, and N. G. Laing. Congenital Titinopathy: Comprehensive characterization and pathogenic insights. Ann. Neurol., 83(6):1105-1124, 06 2018. [PubMed Central:PMC6105519] [DOI:10.1002/ana.25241] [PubMed:10625306].


E. Gicquel, N. Maizonnier, S. J. Foltz, W. J. Martin, N. Bourg, F. Svinartchouk, K. Charton, A. M. Beedle, and I. Richard. AAV-mediated transfer of FKRP shows therapeutic efficacy in a murine model but requires control of gene expression. Hum. Mol. Genet., 26(10):1952-1965, 05 2017. [PubMed Central:PMC6251615] [DOI:10.1093/hmg/ddx066] [PubMed:23817215].






  • Leducq Foundation
  • LGMD2I Foundation
  • Coalition to Cure Calpainopathy