The preliminary effectiveness of gene therapy for therapeutic angiogenesis in patients with critical limb and chronic myocardial ischemia is both encouraging and promising. The different trials using angiogenic protein and transgenes encoding for VEGF and FGF attest to the safety and effectiveness of these strategies. The current clinical strategies employed for critical limb ischemia and chronic myocardial ischemia constitute an extrapolation from initial applications of gene transfer to animal models with limb ischemia. These results, however, likely have generic implications for strategies of therapeutic neovascularization using alternative candidate genes, vectors, and delivery strategies. Preclinical data supporting the use of other VEGF-1 isoforms (121) other VEGF genes (122), and FGF (25,133) has been reported and are actively being studied in ongoing clinical trials. Furthermore, the relative merits of gene transfer versus recombinant protein administration remain to be clarified. In addition, the ideal vector for gene transfer has yet to be determined. There continues to be concern about potential carcinogen-esis in patients treated with retroviral vectors as seen in a recent trial of gene therapy utilizing a retroviral vector for the treatment of severe combined immunodeficiency syndrome (SCIDS) (FDA communication). A naked DNA vector strategy may have safety advantages in the early stages of cardiovascular gene therapy.
The otherwise negative primary endpoint results of the VIVA and FIRST studies using intracoronary ± intravenous protein administration underscore the concern that the pharmacokinetics of recombinant protein administered into the vascular space may lead to inadequate local delivery of angiogenic growth factor within the ischemic myocardium. Additional investigations comparing doses of recombinant protein and routes of delivery will be required to resolve this issue. Until these studies are complete, the ideal method of achieving therapeutic angiogenesis remains unknown. In addition, results of phase 1 studies, designed by definition to assess safety, must be interpreted with caution. Typically, the number of patients enrolled in such trials is relatively small, and for those lacking a control group a placebo effect cannot be excluded. For studies in which recombinant protein or gene is administered in conjunction with conventional revascularization, it may be difficult to determine the relative contributions of the angiogenic agent versus bypass surgery to the symptomatic response.
It is clear, however, that site-specific VEGF gene transfer can be used to achieve physiologically meaningful therapeutic modulation of vascular disorders and specifically that intramyocardial injection of naked plasmid DNA achieves constitutive overexpression of VEGF sufficient to induce therapeutic angiogenesis in selected patients with critical limb ischemia. Of note, there was no evidence of immunological toxicity in either our intra-arterial animal studies or our human clinical experience utilizing naked plasmid DNA encoding for VEGF. Furthermore, at this early stage of clinical trials into myocardial gene therapy, it has been shown that direct myocardial gene transfer utilizing different doses of naked plasmid DNA encoding for VEGF165 and VEGF-2 as well as intracoronary FGF-5 carried by an adenovirus vector can be performed safely with augmentation of myocardial perfusion. The catheter-based delivery of plasmid DNA is an attractive and safe option. In terms of safety, no operative complications and no aggravated deterioration in eyesight due to diabetic retinopathy (124) have been observed in patients treated with phVEGF165 gene transfer. With specific regard to mortality, it should be noted that the cumulative mortality for the 85 patients with class 3 or 4 angina undergoing operative or percutaneous naked DNA gene transfer of VEGF-1 or VEGF-2 has been 3 of 85 (3.5%) at up to 33 mo follow-up. This compares favorably with an average 11-13% 1-yr mortality for a similar group of almost 1000 patients receiving laser myocardial revascularization or continued medical therapy in five con temporary controlled studies (125-129). Ongoing clinical studies will determine the potential for neovascularization gene therapy to be performed by nonsurgical, catheter-based delivery, although early results are encouraging from a therapeutic standpoint.
For the most part, clinical studies of therapeutic angiogenesis have been restricted to patients with myocardial or limb ischemia who have no other options. Although this is the group to target in the near future, it is not difficult to foresee a time when a significant populations of patients who undergo bypass surgery but are not optimal candidates for that procedure may be eligible for therapeutic angiogenesis. The latter might be performed at an earlier stage of disease, and the potential for repeat treatment may translate into a greater possibility of a successful outcome.
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