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


CONCLUSIONS
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.
Isner
J M
JM
Division of Cardiovascular Research and the Departments of Medicine, Radiology, and Surgery, St Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Mass 02135, USA.
Baumgartner
I
I
Rauh
G
G
Schainfeld
R
R
Blair
R
R
Manor
O
O
Razvi
S
S
Symes
J F
JF
D000328:Adult; D015901:Angiography, Digital Subtraction; D016228:Endothelial Growth Factors / Q000097:blood / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018014:Gene Transfer Techniques / Q000009:adverse effects; D015316:Genetic Therapy / Q000009:adverse effects; D006439:Hemodynamics; D006801:Humans; D007273:Injections, Intramuscular; D007511:Ischemia / Q000175:diagnosis / Q000209:etiology; D007866:Leg / Q000098:blood supply; D008222:Lymphokines / Q000097:blood / Q000235:genetics*; D018810:Magnetic Resonance Angiography; D008297:Male; D008875:Middle Aged; D018919:Neovascularization, Physiologic; D013919:Thromboangiitis Obliterans / Q000150:complications / Q000628:therapy*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors