Six-month assessment of a phase I trial of angiogenic gene therapy for the treatment of coronary artery disease using direct intramyocardial administration of an adenovirus vector expressing the VEGF121 cDNA

Abstract

Objective: To summarize the 6-month follow-up of a cohort of patients with clinically significant coronary artery disease who received direct myocardial injection of an E1-E3- adenovirus (Ad) gene transfer vector (Ad(GV)VEGF121.10) expressing the human vascular endothelial growth factor (VEGF) 121 cDNA to induce therapeutic angiogenesis.

Background: Therapeutic angiogenesis describes a novel approach to the treatment of vascular occlusive disease that uses the administration of growth factors known to induce neovascularization of ischemic tissues.

Methods: Direct myocardial injection of Ad(GV)VEGF121.10 into an area of reversible ischemia was carried out in 21 patients as an adjunct to conventional coronary artery bypass grafting (group A, n = 15) or as sole therapy using a minithoracotomy (group B, n = 6).

Results: No evidence of systemic or cardiac-related adverse events related to vector administration was observed up to 6 months after therapy. Trends toward improvement in angina class and exercise treadmill testing at 6-month follow-up in the sole therapy group suggest the effects of this therapy are persistent for > or =6 months.

Conclusions: This study suggests that direct myocardial administration of Ad(GV)VEGF121.10 appears to be well tolerated in patients with clinically significant coronary artery disease. Initiation of phase II evaluation of this therapy appears warranted.

Figure 1. Assessment of anti-Ad5 neutralizing antibody titers⁻¹ before therapy and after intramyocardial administration of Ad_GVVEGF121.10. (A) Patients receiving Ad_GVVEGF121.10 as an adjunct to CABG. (B) Patients receiving Ad_GVVEGF121.10 as sole therapy. Data are presented as titer⁻¹. Data for group A have been previously reported for the 4 × 10⁸ pu dose ≤90 days and for all other doses ≤30 days (Harvey et al 1999 17).

Figure 2. Assessment of angina before therapy and 1 and 6 months after intramyocardial administration of Ad_GVVEGF121.10 in the sole therapy/minithoracotomy group. (A) Canadian Cardiovascular Society angina classifications before and 1 and 6 months after Ad_GVVEGF121.10 therapy. (B) Sublingual nitroglycerin use assessed on a weekly basis. Pretherapy and 30-day data have been previously reported (Rosengart et al 1999 14).