Duchenne muscular dystrophy (DMD) is an X-linked, lethal
disease caused by mutations of the dystrophin gene. No
effective therapy is available, 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
muscle. Retroviral producer cells, which release a vector
carrying the therapeutically active dystrophin minigene,
were mitotically inactivated and transplanted in adult
nude/
mdx
mice. Transplantation of 3
3
10
6
producer cells
in a single site of the tibialis anterior muscle resulted 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 expression was stable for up to
6 mo and led to
a
-sarcoglycan reexpression. Muscle stem
cells could be transduced in vivo using this procedure.
Transduced dystrophic skeletal muscle showed evidence of
active remodeling reminiscent of the genetic normalization
process which takes place in female DMD carriers. Overall,
these results demonstrate that retroviral-mediated dystrophin
gene transfer via transplantation of producer cells is a
valid approach towards the long-term goal of gene therapy
of DMD. (
J. Clin. Invest.
1997. 100:620–628
.
