Systemic delivery of genes to striated muscles using adeno-associated viral vectors

Nat Med. 2004 Aug;10(8):828-34. doi: 10.1038/nm1085. Epub 2004 Jul 25.

Abstract

A major obstacle limiting gene therapy for diseases of the heart and skeletal muscles is an inability to deliver genes systemically to muscles of an adult organism. Systemic gene transfer to striated muscles is hampered by the vascular endothelium, which represents a barrier to distribution of vectors via the circulation. Here we show the first evidence of widespread transduction of both cardiac and skeletal muscles in an adult mammal, after a single intravenous administration of recombinant adeno-associated virus pseudotype 6 vectors. The inclusion of vascular endothelium growth factor/vascular permeability factor, to achieve acute permeabilization of the peripheral microvasculature, enhanced tissue transduction at lower vector doses. This technique enabled widespread muscle-specific expression of a functional micro-dystrophin in the skeletal muscles of dystrophin-deficient mdx mice, which model Duchenne muscular dystrophy. We propose that these methods may be applicable for systemic delivery of a wide variety of genes to the striated muscles of adult mammals.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Capillary Permeability / drug effects*
  • Chromatography, Affinity
  • DNA Primers
  • Disease Models, Animal
  • Dystrophin / metabolism
  • Endothelium / metabolism
  • Genetic Therapy / methods*
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / metabolism*
  • Injections, Intravenous
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence
  • Muscle Contraction / physiology
  • Muscle, Skeletal / metabolism*
  • Muscular Dystrophy, Duchenne / therapy*
  • Parvovirus / metabolism
  • Vascular Endothelial Growth Factor A / pharmacology*

Substances

  • DNA Primers
  • Dystrophin
  • Vascular Endothelial Growth Factor A