DIRECT RETROVIRAL-MEDIATED TRANSFER OF A DYSTROPHIN MINIGENE INTO MDX MOUSE MUSCLE INVIVO

At the cellular level, the primary pathology in Duchenne muscular dystrophy (DMD) is caused by deficiency of the sarcolemmal-associated protein, dystrophin, in the striated musculature. Here we describe the somatic transfer and long-term expression of a human dystrophin minigene corresponding to a mild Becker muscular dystrophy (BMD) phenotype in skeletal muscle tissues of the dystrophin-deficient mdx mouse by direct retroviral transduction. Following a single intramuscular injection of recombinant retrovirus, sarcolemmal expression of dystrophin was observed in an average of approximately 6% of myofibres in treated tibialis anterior muscles and was associated with activated reappearance of at least one component (43kD) of the dystrophin-glycoprotein membrane complex (DGC). Furthermore, expression of recombinant dystrophin was observed in muscle tissues up to 9 months after treatment and a significant enhancement of retrovirus-mediated myofibre transduction was obtained in mdx muscle undergoing experimentally-induced regeneration. The results clearly demonstrate that retroviral transduction of activated satellite cells in regenerating skeletal muscle is a feasible route for direct and stable dystrophin gene transfer into muscle tissues in vivo.