Therapeutic Angiogenesis Revisited

I read the recent study by Favaloro et al. with great interest. More than a decade ago, my collaborators and I investigated the use of therapeutic angiogenesis in preclinical models and in experimental clinical trials. Unfortunately, our efforts have not been clinically successful. Angiogenesis is a process whereby blood vessels sprout and develop from pre-existing vascular networks to compensate for deficiencies in the blood supply to tissues [1]. While working at the Washington Heart Institute some years ago, we experimented extensively with plasmids and gene-based vectors that encoded angiogenic cytokines such as basic and acidic fibroblast growth factors, vascular endothelial growth factors (VEGF, e.g., the 121 and 165 isoforms), angiopoietin-1 (Ang1), hypoxia-inducible factor-1a, and others [2]. We also experimented with cellular elements such as bone marrow-derived progenitor cells, combinations of growth factors and stem cells, and cellular secretory fluids and mixtures of other experimental products [3]. In addition, we developed unique navigation catheters that delivered the presumed angiogenic compounds into severely ischemic zones within the viable myocardium [2,3]. This research aimed to promote substantial neovascularization in the ischemic zones of the heart and peripheral limbs. We were not the only researchers striving to achieve this goal; indeed, several other groups of investigators were intensively involved in parallel research endeavors. By the late 1990s, I was one of the organizers of a scientific “angiogenesis summit” in Washington, DC. Angiogenesis investigators came together to present their work and to share their knowledge and experiences. For those of us working on experimental therapeutic cardiovascular angiogenesis, this was a very promising and exciting time. However, the following years yielded disappointing clinical results, including negative or unpersuasive randomized clinical trials [4– 6]. In my view, the experimental clinical studies left us with more questions than answers. It was unclear which factor or combination of factors was likely to lead to clinically relevant angiogenesis and whether proteins, gene-based therapies, or even progenitor cells should be used. The optimal system for delivery to the heart, the most suitable candidates for human trials, the most relevant clinical endpoint, and the imaging modalities best suited for monitoring results also remained unclear. In addition, there were some local and systemic safety hazards associated with these experimental treatments that needed to be addressed before more extensive clinical trials could be conducted [7]. The elusive balance between promoting and blocking angiogenic signals was not fully understood, and it was apparent that more basic research was needed before clinical research resumed. Meanwhile, investigation of new molecular targets and principles indicated that a single angiogenic product might be insufficient for eliciting therapeutic angiogenesis [8]. More recently, we conducted a randomized, double-blind, placebo-controlled gene therapy study using a replication-deficient adenovirus and genes encoding VEGF121 [9]. The study was terminated prematurely as we were unable to detect changes in the time to ischemic threshold or myocardial perfusion compared to sham injections in patients with refractory myocardial ischemia. In the current report, Favaloro et al. assessed the safety and efficacy of intramyocardial injection of a plasmid encoding VEGF165 (pVEGF165) into patients with refractory coronary artery disease [10]. The GENESIS I trial posited that higher dose VEGF165 (3.8 mg compared to lower doses used in previous negative trials) would improve treatment efficacy without compromising safety. Ten ischemic patients with moderate to severe angina that was not amenable for revascularization received a total pVEGF165 dose of 3.8 mg at 10