Treatment of thromboangiitis obliterans (Buerger's disease) by intramuscular gene transfer of vascular endothelial growth factor: Preliminary clinical results

Purpose: Thromboangiitis obliterans (TAO), or Buerger's disease, a distinct form of vascular occlusive disease that afflicts the peripheral arteries of young smokers, is often characterized by an inexorable downhill course even in patients who discontinue smoking once a stage of critical limb ischemia associated with ulceration or gangrene is reached. As part of a phase I clinical trial to document the safety and efficacy of intramuscular gene transfer of naked plasmid DNA-encoding vascular endothelial growth factor (phVEGF₁₆₅) in the treatment of critical limb ischemia, we treated TAO in 6 patients. Methods: Seven limbs in 6 patients (3 men, 3 women; mean age, 33 years; range, 33 to 51 years) who satisfied the criteria for TAO and had signs or symptoms of critical limb ischemia were treated twice, 4 weeks apart, with 2 or 4 mg of phVEGF₁₆₅, which was administered by direct intramuscular injection at 4 arbitrarily selected sites in the ischemic limb. The gene expression was documented by enzyme-linked immunosorbent assay that was performed on peripheral blood samples. Results: The ulcers that were nonhealing for more than 1 month healed completely in 3 of 5 limbs after the intramuscular phVEGF₁₆₅ gene therapy. Nocturnal rest pain was relieved in the remaining 2 patients, although both continue to have claudication. The evidence of the improved perfusion to the distal ischemic limb included an increase of more than 0.1 in the ankle brachial index in 3 limbs, an improved flow shown with magnetic resonance imaging in 7 of the 7 limbs, and newly visible collateral vessels shown with serial contrast angiography in 7 of the 7 limbs. The adverse consequences of the phVEGF₁₆₅ gene transfer were limited to transient ankle or calf edema in 3 of the 7 limbs. Two patients with advanced distal forefoot gangrene ultimately required below-knee amputation despite the evidence of improved perfusion. A histologic section disclosed the classic pathologic findings of TAO. Conclusion: Therapeutic angiogenesis with phVEGF₁₆₅ gene transfer, if instituted before the development of forefoot gangrene, may provide a novel therapy for patients with advanced Buerger's disease that is unresponsive to standard medical or surgical treatment methods.