Gene therapy progress and prospects: therapeutic angiogenesis for ischemic cardiovascular disease

Abstract

During the past decade, both in vitro and in vivo studies have provided new insights into the cellular and molecular mechanisms that govern angiogenesis and arteriogenesis. However, therapeutic angiogenesis clinical trials using recombinant protein or gene therapy formulations of single angiogenic growth factors have yielded at best only modest success to date. Among the second generation of angiogenic agents are therapeutic transgenes that enhance expression of two or more proangiogenic cytokines. These include synthetic constructs that mimic that activity of endogenous transcriptional regulators and other upstream, regulatory factors that have the potential to induce formation of morphologically and physiologically functional vessels. These agents are now beginning to be evaluated in clinical trials for patients with advanced ischemic cardiac and peripheral vascular disease.

Redox-Dependent Mechanisms in Coronary Collateral Growth: The “Redox Window” Hypothesis

“…This was apparent in our previous work in which oxidative stress adversely affected VEGF signaling and blocked the angiogenic actions of this factor (85). The clinical implication of these observations relates to the failed trials of ''therapeutic angiogenesis'' (the term angiogenesis under these circumstances is a misnomer because the interventions were intended to stimulate collateral growth) (3,4,55,79,95,111), where growth-factor gene therapy or administration of recombinant proteins was attempted in patients to stimulate coronary collateral growth. Perhaps the outcome of these trials would have been different had the investigators implemented an intervention to correct the background oxidative stress.…”

Local and Sustained Vascular Endothelial Growth Factor Delivery for Angiogenesis Using an Injectable System

“…Angiogenesis promotes capillary sprouting and extension from preexisting blood vessels, leading to new blood vessel formation (5). Various angiogenic molecules, stem cells or endothelial precursor cells, and genes have been utilized to treat ischemic vascular diseases (6)(7)(8)(9). In addition, recent studies report that angiogenesis is useful for tissue engineering applications, especially for large tissue formation (10)(11)(12).…”

Approaches in Gene Therapy of Cancer and Cardiovascular Diseases

“…The second generation of angiogenic gene therapeutics is represented by constructs enabling the expression of two or more proangiogenic cytokines. Analogous to gene therapy using the master regulatory gene HIF-1 , these "multivalent" approaches may provide a benefit against the classical "monovalent" ones (Vincent et al, 2007). Overall, we might conclude that only slight clinical benefit of gene therapy in cardiovascular diseases has been observed so far on the level of multicenter, randomized, placebocontrolled clinical trials.…”

“…However, in the clinical studies with genes encoding for individual proangiogenic growth factors (similar to recombinant proteins) only moderate success has been observed so far, thus creating a space for development of new vectors and alternative approaches (Vincent et al, 2007). Progress in the field of gene therapy for cardiovascular disease has been modest; one of the key reasons for this limited progress is the lack of gene delivery systems for localizing gene therapy to specific sites to optimize transgene expression and efficacy.…”