Limb-girdle muscular dystrophy (LGMD) is a group of disorders affecting voluntary muscles in children and adults, mainly those around the hips and shoulders. There are at least 19 forms of LGMD, classified by the genetic flaws that appear to cause them. In efforts to develop a gene therapy for LGMD, Dr. Jerry Mendell and colleagues evaluated the safety of a modified adeno-associated virus as a vector to deliver the alpha-sarcoglycan gene to muscle tissue. The primary goal of this small trial was to establish the safety of intramuscular injection of the alpha-sarcoglycan gene into a foot muscle. The investigators also evaluated the persistence of gene activity in the muscle, the level of protein produced from the gene and the immune system response to the gene. No adverse events, such as rejection of the therapy by the immune system, occurred during the trial, confirming that the approach is safe in patients with the alpha-sarcoglycan-deficient form of LGMD. Moreover, all three trial participants, aged 12-14, produced four to five times the amount of alpha-sarcoglycan protein in the gene-injected foot muscle compared to the amount in the corresponding muscle on the other foot, which received a saline solution. The transferred genes continued to produce the protein for at least six months after treatment. The data from this study has potential relevance for other muscle diseases and for diseases in which muscle tissue can be used to secrete therapeutic proteins into the bloodstream. These results demonstrate the feasibility of gene therapy to treat limb-girdle muscular dystrophy and are the first to show promise beyond safety alone.

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