Isner J M, Baumgartner I, Rauh G, Schainfeld R, Blair R, Manor O, Razvi S, Symes J F
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.
J Vasc Surg. 1998 Dec;28(6):964-73; discussion 73-5. doi: 10.1016/s0741-5214(98)70022-9.
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.
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.
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.
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.
血栓闭塞性脉管炎（TAO），即伯格氏病，是一种独特的血管闭塞性疾病，困扰着年轻吸烟者的外周动脉，其特点通常是即便患者一旦进入与溃疡或坏疽相关的严重肢体缺血阶段就戒烟，病情仍会不可避免地恶化。作为一项I期临床试验的一部分，该试验旨在记录裸质粒DNA编码血管内皮生长因子（phVEGF165）肌肉注射基因转移治疗严重肢体缺血的安全性和有效性，我们对6例血栓闭塞性脉管炎患者进行了治疗。
6例患者（3男3女；平均年龄33岁；范围33至51岁）的7条肢体符合血栓闭塞性脉管炎标准且有严重肢体缺血的体征或症状，每隔4周接受两次2或4毫克phVEGF165治疗，通过在缺血肢体的4个任意选定部位直接肌肉注射给药。通过对外周血样本进行酶联免疫吸附测定记录基因表达情况。
5条肢体中，有3条在接受肌肉注射phVEGF165基因治疗后，超过1个月未愈合的溃疡完全愈合。其余2例患者夜间静息痛得到缓解，尽管两人仍有间歇性跛行。远端缺血肢体灌注改善的证据包括：3条肢体的踝肱指数增加超过0.1；7条肢体中的7条经磁共振成像显示血流改善；7条肢体中的7条经系列造影血管造影显示有新出现的可见侧支血管。phVEGF165基因转移的不良后果仅限于7条肢体中的3条出现短暂的踝部或小腿水肿。尽管有灌注改善的证据，但2例晚期前足坏疽患者最终仍需要进行膝下截肢。组织学切片显示了血栓闭塞性脉管炎的典型病理表现。
如果在发生前足坏疽之前进行phVEGF165基因转移的治疗性血管生成，可能为对标准药物或手术治疗方法无反应的晚期伯格氏病患者提供一种新的治疗方法。
