GENETIC CORRECTION OF DYSTROPHIN DEFICIENCY AND SKELETAL-MUSCLE REMODELING IN ADULT MDX MOUSE VIA TRANSPLANTATION OF RETROVIRAL PRODUCER CELLS

Duchenne muscular dystrophy (DMD) is an X-linked, lethal disease cause d by mutations of the dystrophin gene, No effective therapy is availab le, but dystrophin gene transfer to skeletal muscle has been proposed as a treatment for DMD, We have developed a strategy for efficient in vivo gene transfer of dystrophin cDNA into regenerating skeletal muscl e, Retroviral producer cells, which release a vector carrying the ther apeutically active dystrophin minigene, were mitotically inactivated a nd transplanted in adult nude/mdx mice, Transplantation of 3 x 10(6) p roducer cells in a single site of the tibialis anterior muscle resulte d in the transduction of between 5.5 and 18% total muscle fibers, The same procedure proved also feasible in immunocompetent mdx mice under short-term pharmacological immunosuppression, Minidystrophin expressio n was stable for up to 6 mo and led to alpha-sarcoglycan reexpression. Muscle stem cells could be transduced in vivo using this procedure, T ransduced dystrophic skeletal muscle showed evidence of active remodel ing reminiscent of the genetic normalization process which takes place in female DMD carriers, Overall, these results demonstrate that retro viral-mediated dystrophin gene transfer via transplantation of produce r cells is a valid approach towards the long-term goal of gene therapy of DMD.