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

Hideki Amano, Neil R. Hackett, Robert J. Kaner, Paul Whitlock, Todd K. Rosengart, Ronald Crystal

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)716-724
Number of pages9
JournalMolecular Therapy
Volume12
Issue number4
DOIs
Publication statusPublished - 1 Oct 2005
Externally publishedYes

Fingerprint

Genetic Therapy
Vascular Endothelial Growth Factor A
Protein Isoforms
Complementary DNA
Safety
Genes
Physiologic Neovascularization
Alternative Splicing
Pulmonary Edema
Adenoviridae
Intravenous Administration
Exons
Ischemia
Extremities
Growth
Neoplasms

Keywords

  • Adenovirus
  • Angiogenesis
  • Gene therapy
  • Safety
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Molecular Biology

Cite this

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. / Amano, Hideki; Hackett, Neil R.; Kaner, Robert J.; Whitlock, Paul; Rosengart, Todd K.; Crystal, Ronald.

In: Molecular Therapy, Vol. 12, No. 4, 01.10.2005, p. 716-724.

Research output: Contribution to journalArticle

Amano, Hideki ; Hackett, Neil R. ; Kaner, Robert J. ; Whitlock, Paul ; Rosengart, Todd K. ; Crystal, Ronald. / 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. In: Molecular Therapy. 2005 ; Vol. 12, No. 4. pp. 716-724.
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