Alteration of splicing signals in a genomic/cDNA hybrid VEGF gene to modify the ratio of expressed VEGF isoforms enhances safety of angiogenic gene therapy

Mol Ther. 2005 Oct;12(4):716-24. doi: 10.1016/j.ymthe.2005.03.031.


Vascular endothelial growth factor (VEGF)-mediated physiological angiogenesis results from the concerted action of three major VEGF isoforms (VEGF121, 165, 189), which arise from alternate splicing. We have previously shown that expression of a mixture of VEGF isoforms via gene transfer is considerably more potent than expression of a single VEGF isoform. To test the hypothesis that different mixtures of VEGF isoforms may offer the same therapeutic benefit with a better safety profile, we compared the efficacy and safety of an adenovirus gene transfer vector expressing the three major VEGF isoforms (AdVEGF-All) in the normal ratio to those of AdVEGF-All6A+, in which the splicing sequences for exon 6A were altered to promote expression of VEGF189 at the expense of VEGF121. Both vectors were equally potent in mediating recovery of hind-limb blood flow following experimental ischemia. By contrast, intravenous administration of AdVEGF-All6A+ yielded enhanced survival and a lower capacity to support tumor growth compared to AdVEGF-All, and intratracheal administration of AdVEGF-All6A+ resulted in less pulmonary edema than that of AdVEGF-All. We conclude that AdVEGF-All and AdVEGF-All6A+ are similar in potency but that AdVEGF-All6A+ is safer. This suggests that AdVEGF-All6A+ may be the preferred candidate for clinical development.

Publication types

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

MeSH terms

  • Adenoviridae / genetics*
  • Alternative Splicing / genetics
  • Angiogenesis Inducing Agents
  • Animals
  • DNA, Complementary
  • Gene Expression
  • Genetic Therapy* / adverse effects
  • Genetic Vectors*
  • Humans
  • Injections, Intravenous
  • Ischemia / pathology
  • Ischemia / therapy*
  • Mice
  • Mice, Inbred BALB C
  • Neovascularization, Physiologic / genetics*
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Vascular Endothelial Growth Factors / genetics*
  • Vascular Endothelial Growth Factors / metabolism


  • Angiogenesis Inducing Agents
  • DNA, Complementary
  • Protein Isoforms
  • Vascular Endothelial Growth Factors