Treatment of thromboangiitis obliterans (Buerger's disease) by intramuscular gene transfer of vascular endothelial growth factor: Preliminary clinical results
Treatment of thromboangiitis obliterans (Buerger's disease) by intramuscular gene transfer of vascular endothelial growth factor: Preliminary clinical results
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DOI：
10.1016/s0741-5214(98)70022-9
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发表时间：
1998-12-01
影响因子：
4.3
通讯作者：
Symes, JF
中科院分区：
文献类型：
--
作者：
Isner, JM;Baumgartner, I;Symes, JF
目的：血栓闭塞性脉管炎(TAO)，或Buerger病，是一种独特的血管闭塞性疾病，困扰年轻吸烟者的外周动脉，即使患者一旦达到与溃疡或坏疽相关的严重肢体缺血阶段，也往往以不可阻挡的下坡过程为特征。作为I期临床试验的一部分，为了证明肌肉内转移编码血管内皮生长因子(PhVEGF)的裸质粒DNA(165)治疗严重肢体缺血的安全性和有效性，我们对6例TAO患者进行了治疗。方法：6例患者(男3例，女3例；平均年龄33岁；年龄33~51岁)符合TAO标准并有严重肢体缺血的体征或症状的患者接受2次治疗，间隔4周，用2 mg或4 mg phVEGF(165)直接肌肉注射到缺血肢体的4个部位。结果：经肌肉注射phVEGF(165)基因治疗后，1个月以上未愈合的5条肢体中有3条完全愈合。其余2名患者夜间休息疼痛缓解，尽管两人仍有跛行。3条患肢踝臂指数增加0.1以上，7条患肢磁共振显示7条患肢血流改善，7条患肢连续增强血管造影显示新的侧支循环。PhVEGF165基因转移的不良后果仅限于7个肢体中的3个肢体出现一过性脚踝或小腿浮肿。两名患有晚期前足远端坏疽的患者，尽管有改善血流灌注的证据，最终还是需要在膝盖以下截肢。组织学切片显示了TAO的典型病理改变。结论：如果在前足坏疽发生之前进行phVEGF(165)基因转移的治疗性血管生成，可能为对标准内科或外科治疗无效的晚期Buerger病患者提供一种新的治疗方法。
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 (phVEGF(165)) 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 phVEGF(165), 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 phVEGF(165) 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 tranfer 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 phVEGF(165) 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.