Capsid-modified adenoviral vectors for improved muscle-directed gene therapy

Hum Gene Ther. 2012 Oct;23(10):1065-70. doi: 10.1089/hum.2012.003. Epub 2012 Aug 13.

Abstract

Skeletal muscle represents an attractive target tissue for adenoviral gene therapy to treat muscle disorders and as a production platform for systemic expression of therapeutic proteins. However, adenovirus serotype 5 vectors do not efficiently transduce adult muscle tissue. Here we evaluated whether capsid modifications on adenoviral vectors could improve transduction in mature murine muscle tissue. First-generation and helper-dependent serotype 5 adenoviral vectors featuring the serotype 3 knob (5/3) showed significantly increased transduction of skeletal muscle after intramuscular injection in adult mice. Furthermore, we showed that full-length dystrophin could be more efficiently transferred to muscles of mdx mice using a 5/3-modified helper-dependent adenoviral vector. In contrast to first-generation vectors, helper-dependent adenoviral vectors mediated stable marker gene expression for at least 1 year after intramuscular injection. In conclusion, 5/3 capsid-modified helper-dependent adenoviral vectors show enhanced transduction in adult murine muscle tissue and mediate long-term gene expression, suggesting the suitability of these vectors for muscle-directed gene therapy.

Publication types

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

MeSH terms

  • Adenoviridae / genetics*
  • Animals
  • Capsid / metabolism*
  • Gene Expression
  • Genetic Therapy*
  • Genetic Vectors / genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred mdx
  • Muscle, Skeletal / metabolism*
  • Organ Specificity
  • Time Factors