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 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 o...

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Bibliographic Details
Published in:	The Journal of clinical investigation Vol. 100; no. 3; pp. 620 - 628
Main Authors:	Fassati, A, Wells, D J, Sgro Serpente, P A, Walsh, F S, Brown, S C, Strong, P N, Dickson, G
Format:	Journal Article
Language:	English
Published:	United States 01-08-1997
Subjects:	Animals Cell Transplantation DNA, Complementary - genetics Dystrophin - deficiency Dystrophin - genetics Female Gene Transfer Techniques Genetic Therapy Genetic Vectors Immunohistochemistry Mice Mice, Inbred mdx Muscle, Skeletal - physiopathology Muscular Dystrophy, Animal - genetics Muscular Dystrophy, Animal - physiopathology Muscular Dystrophy, Animal - therapy Retroviridae
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Summary:	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 x 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 alpha-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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0021-9738
DOI:	10.1172/jci119573