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

Abstract

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.

• Authors: J M Isner, I Baumgartner, G Rauh, R Schainfeld, R Blair, O Manor, S Razvi, J F Symes
• Journal: Journal of vascular surgery (J Vasc Surg) Vol. 28 Issue 6 Pg. 964-73; discussion 73-5 (Dec 1998) ISSN: 0741-5214 [Print] United States
• PMID: 9845647 (Publication Type: Journal Article)

Chemical References

• Endothelial Growth Factors
• Lymphokines
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors

Topics

• Adult
• Angiography, Digital Subtraction
• Endothelial Growth Factors (blood, genetics)
• Enzyme-Linked Immunosorbent Assay
• Female
• Gene Transfer Techniques (adverse effects)
• Genetic Therapy (adverse effects)
• Hemodynamics
• Humans
• Injections, Intramuscular
• Ischemia (diagnosis, etiology)
• Leg (blood supply)
• Lymphokines (blood, genetics)
• Magnetic Resonance Angiography
• Male
• Middle Aged
• Neovascularization, Physiologic
• Thromboangiitis Obliterans (complications, therapy)
• Vascular Endothelial Growth Factor A
• Vascular Endothelial Growth Factors