Résumé :
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Sarcoglycanopathies are recessive muscular disorders caused by defects in a group of transmembrane proteins, known as sarcoglycans, and part of the dystrophinassociated complex. Mutations in the alpha, beta, gamma and delta sarcoglycan genes lead to a similar phenotype and are referred as limb-girdle muscular dystrophies type 2D, 2E, 2C and 2F (LGMD2D, 2E, 2C and 2F) respectively. Dysfunction of one of the sarcoglycan destabilizes the whole sarcoglycan complex, leading to a partial or complete disappearance of the other sarcoglycans at the membrane. To date, no treatment exists for these diseases.The most frequently reported mutation in the alpha-sarcoglycan gene is the substitution of an arginine in position 77 by a cysteine (alpha-R77C). We demonstrated that this mutation encodes a misfolded protein in a human context that fails to be delivered to its proper sarcolemmal localization due to blockade in the endoplasmic reticulum (ER). We hypothesized that, by blocking the ER quality control system, we should be able to rescue the misfolded alpha-sarcoglycan protein at the cell membrane. Consistently, results of our experiments using a heterologous cellular model of sarcoglycan complex formation showed that alpha-mannosidase I inhibitors prevent alpha-R77C degradation by proteasome/ERAD and restore the correct localization of the protein and assembly of the sarcoglycan complex. Subsequently, we were able to rescue other sarcoglycan mutations using the same approach. Following this demonstration, we treated living alpha-sarcoglycan deficient mice humanized for the human R77C protein using AAV transfer with this inhibitor administrated either by intramuscular or intravenous injections or per os. All these routes of administration allow rescuing the R77C membrane localisation and sarcoglycan complex formation. Furthermore, we observed improvement of the muscle histology and force. We now have engaged preclinical studies to evaluate the toxicology and pharmacokinetics of the product with the prospect of future clinical trials for LGMD2 patients carrying mutations which impair sarcoglycan trafficking.
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