Safety evaluation of clinical gene therapy using hepatocyte growth factor to treat peripheral arterial disease
Safety evaluation of clinical gene therapy using hepatocyte growth factor to treat peripheral arterial disease
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DOI：
10.1161/01.hyp.0000136394.08900.ed
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发表时间：
2004-08-01
期刊：
影响因子：
8.3
通讯作者：
Ogihara, T
中科院分区：
文献类型：
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作者：
Morishita, R;Aoki, M;Ogihara, T
血管生成生长因子治疗性血管生成有望成为治疗重度肢体缺血（CLI）的新方法。由于肝细胞生长因子（HGF）具有强大的血管生成活性，我们研究了HGF质粒DNA在CLI患者中的安全性和有效性，作为一项前瞻性开放标记临床试验。对6例被分级为Fontaine III或IV级的动脉硬化闭塞症（n = 3）或Buerger病（n = 3）的CLI患者的缺血肢体进行裸HGF质粒DNA肌肉注射。主要终点是转染后12周的安全性和缺血症状的改善。所有患者均未发现因基因转移引起的严重并发症和不良反应。特别重要的是，在整个试验过程中，没有观察到任何患者出现明显的水肿。此外，在整个治疗期间，所有患者的血清HGF浓度均未发生变化。相比之下，6例患者中有5例的视觉模拟疼痛量表疼痛评分减少超过1 cm。5例患者踝关节压力指数升高大于0.1。4例患者11例缺血性溃疡中8例长径缩小25%。肌内注射裸HGF质粒安全、可行，可成功改善肢体缺血。虽然目前的数据是为了证明作为I期/早期IIa期的安全性，但HGF基因转移的初步临床结果似乎表明作为CLI的唯一治疗方法是有用的。
Therapeutic angiogenesis using angiogenic growth factors is expected to be a new treatment for patients with critical limb ischemia (CLI). Because hepatocyte growth factor (HGF) has potent angiogenic activity, we investigated the safety and efficiency of HGF plasmid DNA in patients with CLI as a prospective open-labeled clinical trial. Intramuscular injection of naked HGF plasmid DNA was performed in ischemic limbs of 6 CLI patients with arteriosclerosis obliterans (n = 3) or Buerger disease (n = 3) graded as Fontaine III or IV. The primary end points were safety and improvement of ischemic symptoms at 12 weeks after transfection. Severe complications and adverse effects caused by gene transfer were not detected in any patients. Of particular importance, no apparent edema was observed in any patient throughout the trial. In addition, serum HGF concentration was not changed throughout the therapy period in all patients. In contrast, a reduction of pain scale of more than 1 cm in visual analog pain scale was observed in 5 of 6 patients. Increase in ankle pressure index more than 0.1 was observed in 5 of 5 patients. The long diameter of 8 of 11 ischemic ulcers in 4 patients was reduced >25%. Intramuscular injection of naked HGF plasmid is safe, feasible, and can achieve successful improvement of ischemic limbs. Although the present data are conducted to demonstrate the safety as phase I/early phase IIa, the initial clinical outcome with HGF gene transfer seems to indicate usefulness as sole therapy for CLI.