Phenotypic improvement of dystrophic muscles by rAAV/microdystrophin vectors is augmented by Igf1 codelivery

Mol Ther. 2005 Sep;12(3):441-50. doi: 10.1016/j.ymthe.2005.04.001.


The absence of dystrophin in Duchenne muscular dystrophy (DMD) leads to sarcolemmal instability and enhances the susceptibility of muscle fibers to contraction-induced injury. Various viral vectors have been used to deliver mini- and microdystrophin expression cassettes to muscles of dystrophin-deficient mdx mice, significantly increasing both the morphological and the functional properties of the muscles. However, dystrophin delivery to adult mdx mice has not yielded a complete rescue of the dystrophic phenotype. Here we investigated a novel strategy involving dual gene transfer of recombinant adeno-associated viral vectors expressing either microdystrophin (rAAV-muDys) or a muscle-specific isoform of Igf-1 (rAAV-mIgf-1). Injection of mdx muscles with rAAV-muDys reduced myofiber degeneration and turnover and increased their resistance to mechanical injury, but did not increase muscle mass or force generation. Injection of mdx muscles with rAAV-mIgf-1 led to increased muscle mass, but did not provide protection against mechanical injury or halt myofiber degeneration, leading to loss of the vector over time. In contrast, co-injection of the rAAV-muDys and rAAV-mIgf-1 vectors resulted in increased muscle mass and strength, reduced myofiber degeneration, and increased protection against contraction-induced injury. These results suggest that a dual-gene, combinatorial strategy could enhance the efficacy of gene therapy of DMD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • DNA / metabolism
  • DNA, Complementary / metabolism
  • Dependovirus / genetics*
  • Disease Models, Animal
  • Dystrophin / genetics*
  • Gene Transfer Techniques
  • Genetic Therapy / methods*
  • Humans
  • Hypertrophy
  • Image Processing, Computer-Assisted
  • Immunohistochemistry
  • Insulin-Like Growth Factor I / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred mdx
  • Models, Genetic
  • Molecular Sequence Data
  • Muscles / pathology
  • Muscular Dystrophies / therapy*
  • Phenotype
  • Plasmids / metabolism
  • RNA / metabolism
  • RNA, Messenger / metabolism


  • DNA, Complementary
  • Dystrophin
  • RNA, Messenger
  • RNA
  • Insulin-Like Growth Factor I
  • DNA

Associated data

  • GENBANK/AY878192
  • GENBANK/AY878193