A. Fassati et al., GENETIC CORRECTION OF DYSTROPHIN DEFICIENCY AND SKELETAL-MUSCLE REMODELING IN ADULT MDX MOUSE VIA TRANSPLANTATION OF RETROVIRAL PRODUCER CELLS, The Journal of clinical investigation, 100(3), 1997, pp. 620-628
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.