doi: 10.1161/CIRCRESAHA.109.200386
© 2009 American Heart Association, Inc.
Review |
Human Studies of Angiogenic Gene Therapy
From the Feinberg Cardiovascular Research Institute (R.G., J.T., D.W.L.), Northwestern University School of Medicine and Northwestern Memorial Hospital, Chicago, Ill; and Department of Cardiology and Angiology (J.T.), Hannover Medical School, Germany.
Correspondence to Douglas W. Losordo, MD, Feinberg Cardiovascular Research Institute, Northwestern University, Tarry 14-725, 303 East Chicago Ave, Chicago, IL 60611. E-mail d-losordo{at}northwestern.edu
This Review is part of a thematic series on Cardiovascular Gene Therapy, which includes the following articles: Gene Therapy in Heart Failure [2008;102:1458–1470]
Human Studies of Angiogenic Gene Therapy
Gene Therapy for Cardioprotection
Gene Therapy for Arrhythmias
New Vectors for Gene Transfer
Gene Correction Strategies
The Editors of Circulation Research
Abstract: Despite significant advances in medical, interventional, and surgical therapy for coronary and peripheral arterial disease, the burden of these illnesses remains high. To address this unmet need, the science of therapeutic angiogenesis has been evolving for almost two decades. Early preclinical studies and phase I clinical trials achieved promising results with growth factors administered as recombinant proteins or as single-agent gene therapies, and data accumulated through 10 years of clinical trials indicate that gene therapy has an acceptable safety profile. However, more rigorous phase II and phase III clinical trials have failed to unequivocally demonstrate that angiogenic agents are beneficial under the conditions and in the patients studied to date. Investigators have worked to understand the biology of the vascular system and to incorporate their findings into new treatments for patients with ischemic disease. Recent gene- and cell-therapy trials have demonstrated the bioactivity of several new agents and treatment strategies. Collectively, these observations have renewed interest in the mechanisms of angiogenesis and deepened our understanding of the complexity of vascular regeneration. Gene therapy that incorporates multiple growth factors, approaches that combine cell and gene therapy, and the administration of "master switch" agents that activate numerous downstream pathways are among the credible and plausible steps forward. In this review, we examine the clinical development of angiogenic gene therapy, summarize several of the lessons learned during the conduct of these trials, and suggest how this prior experience may guide the conduct of future preclinical investigations and clinical trials.
Key Words: gene therapy • angiogenesis • clinical trials