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.
| Publication Type | Academic Article |
| Authors | Amano H, Hackett N, Kaner R, Whitlock P, Rosengart T, Crystal R |
| Journal | Mol Ther |
| Volume | 12 |
| Issue | 4 |
| Pagination | 716-24 |
| Date Published | 10/01/2005 |
| ISSN | 1525-0016 |
| Keywords | Adenoviridae, Genetic Therapy, Genetic Vectors, Ischemia, Neovascularization, Physiologic, Vascular Endothelial Growth Factors |
| 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. |
| DOI | 10.1016/j.ymthe.2005.03.031 |
| PubMed ID | 16039163 |