Therapeutic angiogenesis due to balanced single‐vector delivery of VEGF and PDGF‐BB

• Published in: The FASEB journal 2012-06, Vol.26 (6), p.2486-2497
• Main Authors: Banfi, Andrea, Degenfeld, Georges, Gianni‐Barrera, Roberto, Reginato, Silvia, Merchant, Milton J., McDonald, Donald M., Blau, Helen M.
• Format: Article
• Language: English
• Subjects: adenoviral vectors; Adenoviridae - genetics; Animals; gene therapy; Gene Transfer Techniques; Genetic Therapy - methods; Genetic Vectors; HEK293 Cells; Hindlimb - blood supply; Humans; ischemia; Male; Mice; Mice, SCID; Muscle, Skeletal - blood supply; Neovascularization, Physiologic - physiology; Platelet-Derived Growth Factor - therapeutic use; Proto-Oncogene Proteins c-sis - administration & dosage; Proto-Oncogene Proteins c-sis - therapeutic use; Research Communications; Vascular Endothelial Growth Factor A - administration & dosage; Vascular Endothelial Growth Factor A - therapeutic use
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.11-197400

Therapeutic angiogenesis by delivery of vascular growth factors is an attractive strategy for treating debilitating occlusive vascular diseases, yet clinical trials have thus far failed to show efficacy. As a result, limb amputation remains a common outcome for muscle ischemia due to severe atherosclerotic disease, with an overall incidence of 100 per million people in the United States per year. A challenge has been that the angiogenic master regulator vascular endothelial growth factor (VEGF) induces dysfunctional vessels, if expressed outside of a narrow dosage window. We tested the hypothesis that codelivery of platelet‐derived growth factor‐BB (PDGF‐BB), which recruits pericytes, could induce normal angiogenesis in skeletal muscle irrespective of VEGF levels. Coexpression of VEGF and PDGF‐BB encoded by separate vectors in different cells or in the same cells only partially corrected aberrant angiogenesis. In marked contrast, coexpression of both factors in every cell at a fixed relative level via a single bicistronic vector led to robust, uniformly normal angiogenesis, even when VEGF expression was high and heterogeneous. Notably, in an ischemic hindlimb model, single‐vector expression led to efficient growth of collateral arteries, revascularization, increased blood flow, and reduced tissue damage. Furthermore, these results were confirmed in a clinically applicable gene therapy approach by adenoviral‐mediated delivery of the bicistronic vector. We conclude that coordinated expression of VEGF and PDGF‐BB via a single vector constitutes a novel strategy for harnessing the potency of VEGF to induce safe and efficacious angiogenesis.—Banfi, A., von Degenfeld, G., Gianni‐Barrera, R., Reginato, S., Merchant, M. J., McDonald, D. M., Blau, H. M. Therapeutic angiogenesis due to balanced single‐vector delivery of VEGF and PDGF‐BB. FASEB J. 26, 2486‐2497 (2012). www.fasebj.org