Résumé :
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BACKGROUND Gamma-sarcoglycanopathy or limb girdle muscular dystrophy type 2C (LGMD 2C) is an untreatable disease caused by autosomal recessively inherited mutations of the -sarcoglycan gene (SGC). METHODS Nine non-ambulatory LGMD2C patients (2 M, 7 F, age 27 y [16 to 38]) with del525T homozygous mutation of the SGC gene and no SGC immunostaining on muscle biopsy were divided into 3 equal groups to receive 3 escalating doses of an AAV1 vector expressing the human SGC gene under the control of the desmin promoter, by local injection into the extensor carpi radialis muscle. The first group received a single injection of 3x109 viral genomes (vg) in 100 ml, the second group received a single injection of 1.5x1010 vg in 100ml, and the third group received three simultaneous 100-ml injections at the same site, delivering a total dose of 4.5x1010 vg. RESULTS No serious adverse effects occurred during 6 months of follow-up. All 9 patients became AAV1-seropositive and one developed a cytotoxic response to the AAV1 capsid. Thirty days later, immunohistochemical analysis of injected-muscle biopsy specimens showed SGC expression in 5 patients (4.7% to 10.5% positively stained fibers), while RT-PCR detected SGC mRNA in all 3 patients who received the highest dose. SGC protein was detected by Western blot in one patient. CONCLUSIONS SGC protein expression can be induced in LGMD2C patients by AAV1 gene transfer, with no adverse effects, paving the way for gene therapy of hereditary muscle diseases.
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