We sought to investigate the safety and efficacy of intramuscular gene therapy with vascular endothelial growth factor (VEGF) in patients with chronic critical leg ischemia.

Gene transfer was performed in 24 limbs of 21 patients with rest pain, some of whom also had nonhealing ischemic ulcers (n = 16) due to occlusive peripheral arterial disease. Between 400 μg and 2000 μg of phVEGF₁₆₅ (400 μg, n = 2; 800 μg, n = 4; 1200 μg, n = 4; 1600 μg, n = 6; and 2000 μg, n = 8) was injected directly into the muscles of the ischemic limb; the same dose was injected 4 weeks later. The ratio of blood pressures at the ankle and brachial artery was measured before and after treatment.

Mean (± SD) plasma levels of VEGF increased significantly from 26 ± 31 pg/mL to 63 ± 56 pg/mL (P <0.005), and the ankle-brachial index improved significantly from 0.58 ± 0.24 to 0.72 ± 0.28 (P <0.001). Magnetic resonance angiography showed qualitative evidence of improved distal flow in 19 limbs (79%). Ischemic ulcers healed or improved markedly in 12 limbs (75%). Rest pain was relieved or improved markedly in 20 limbs (83%). Amputation was performed in two limbs because of wound infection. Complications were limited to transient leg edema in six limbs.

Intramuscular gene therapy with VEGF₁₆₅ for patients with chronic critical leg ischemia is safe, feasible, and effective.