Increased transduction of skeletal muscle cells by fibroblast growth factor-modified adenoviral vectors

Kareena M. Menezes, Hoyin S. Mok, Michael A. Barry

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Gene therapy for Duchenne muscular dystrophy will likely require that the corrective dystrophin gene be delivered to a high fraction of muscle fibers in vivo. Because of the large size of the dystrophin cDNA, adenoviral (Ad) vectors have been developed for this application. However, Ad vectors transduce mature muscle inefficiently in part due to downregulation of Ad receptors on these cells. To circumvent this problem, we have tested fibroblast growth factor-2 (FGF) and insulin-like growth factor (IGF) as ligands for their ability to enhance Ad transduction of muscle cells. In this work, we demonstrate that covalent conjugation of FGF, but not IGF, to AdS vectors mediates substantial increases in transduction of skeletal muscle cells in vitro and dystrophic in vivo. AdS vectors expressing reporter genes were cross-linked to the ligands, using bifunctional polyethylene glycol (PEG) molecules. Ad-PEG-FGF mediated 1000- and 200-fold increases in transduction on C2C12 myoblasts and myotubes in vitro when compared with AdS, Ad-PEG, or Ad-PEG-IGF. When tested in vivo in mdx mice, Ad-PEG-FGF mediated 6-fold higher transduction in skeletal muscle than unmodified AdS. Similar results were seen when using lacZ as a reporter gene to observe transduction qualitatively. These data suggest that FGF may be a useful cell-binding ligand to enhance gene delivery by Ad and other vectors into skeletal muscle for the gene therapy of Duchenne muscular dystrophy and other muscle-related diseases.

Original languageEnglish (US)
Pages (from-to)314-320
Number of pages7
JournalHuman gene therapy
Volume17
Issue number3
DOIs
StatePublished - Mar 1 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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