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Angiogenic gene therapy in patients with nonrevascularizable ischemic heart disease: a phase 2 randomized, controlled trial of AdVEGF121 (AdVEGF121) versus maximum medical treatment

Abstract

The demonstration that angiogenic growth factors can stimulate new blood vessel growth and restore perfusion in animal models of myocardial ischemia has led to the development of strategies designed for the local production of angiogenic growth factors in patients who are not candidates for conventional revascularization. The results of recent clinical trials of proangiogenesis gene therapy have been disappointing; however, significant limitations in experimental design, in particular in gene transfer strategies, preclude drawing definitive conclusions. In the REVASC study cardiac gene transfer was optimized by direct intramyocardial delivery of a replication-deficient adenovirus-containing vascular endothelial growth factor (AdVEGF121, 4 × 1010 particle units (p.u.)). Sixty-seven patients with severe angina due to coronary artery disease and no conventional options for revascularization were randomized to AdVEGF121 gene transfer via mini-thoracotomy or continuation of maximal medical treatment. Exercise time to 1 mm ST-segment depression, the predefined primary end-point analysis, was significantly increased in the AdVEGF121 group compared to control at 26 weeks (P=0.026), but not at 12 weeks. As well, total exercise duration and time to moderate angina at weeks 12 and 26, and in angina symptoms as measured by the Canadian Cardiovascular Society Angina Class and Seattle Angina Questionnaire were all improved by VEGF gene transfer (all P-values at 12 and 26 weeks 0.001). However, if anything the results of nuclear perfusion imaging favored the control group, although the AdVEGF121 group achieved higher workloads. Overall there was no significant difference in adverse events between the two groups, despite the fact that procedure-related events were seen only in the thoracotomy group. Therefore, administration of AdVEGF121 by direct intramyocardial injections resulted in objective improvement in exercise-induced ischemia in patients with refractory ischemic heart disease.

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Acknowledgements

We are grateful for the contribution of Drs Milton Pressler, Angelo Secci, Margaret Samyn and Raphael Pak (Pfizer Global Research and Development) and Grant Yonehiro (GenVec Inc.) for their contributions to this protocol. In addition to the authors, the following individuals were members of the REVASC study group: Marilyn Anger, RN; Lyn Balleza, RN; Richard Bauset, MD; Gopal Bhatnagar, MD; Nancy Camack, RN, BScN, MBA; Ann Campbell, RN; Raymond Cartier, MD; Susan DeRamus, RN, CCRC; Rosemary Dunne, RN; Jim Dutton, MD; Lee Errett, MD; Denise Fortin, RN; Guy Fradet, MD; Stephen Fremes, MD; Ginette Gaudet, RN, Celine Groulx, RN; Linda Harris, RN; Peter Klinke, MD; Michael Kutryk, MD, PhD; Arvind Koshal, MD; Kevin Lachapelle, MD; David Latter, MD; Joanne Leboeuf, RN; Siobhan Loeza-Aceves, RN; Noreen Lounsbury, RN, BN; Debra Lundberg, RN, BN; Andrew Maitland, MD; Beth Marple, RN, BScN; Michel Martin, MD; Brenda Mercier, RN; Lisa Montebruno, RN; Angie Munoz, BN; Dan Muruve, MD; Mary-Lee Myers, MD; Louis Normandin, MD; Cynthia Rice, RN; Guy Rossignol; Jean-Claude Tardif, MD; Patrick Teefy, MD; FRCPC, Violetta Toyota, RN and Wayne Tymchak, MD.

Disclosure: This study was supported by GenVec Inc., Gaithersburg, Maryland; and all authors and institutions received research support for this project from GenVec.

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Stewart, D., Hilton, J., Arnold, J. et al. Angiogenic gene therapy in patients with nonrevascularizable ischemic heart disease: a phase 2 randomized, controlled trial of AdVEGF121 (AdVEGF121) versus maximum medical treatment. Gene Ther 13, 1503–1511 (2006). https://doi.org/10.1038/sj.gt.3302802

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