Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Department of Health Development and Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Curr Gene Ther. 2020;20(1):25-35. doi: 10.2174/1566523220666200516171447.
The objective of this combined analysis of data from clinical trials in Japan, using naked plasmid DNA encoding hepatocyte growth factor (HGF), was to document the safety and efficacy of intramuscular HGF gene therapy in patients with critical limb ischemia (CLI).
HGF gene transfer was performed in 22 patients with CLI in a single-center open trial at Osaka University; 39 patients in a randomized, placebo-controlled, multi-center phase III trial, 10 patients with Buerger's disease in a multi-center open trial; and 6 patients with CLI in a multi-center open trial using 2 or 3 intramuscular injections of naked HGF plasmid at 2 or 4 mg. Resting pain on a visual analogue scale (VAS) and wound healing as primary endpoints were evaluated at 12 weeks after the initial injection. Serious adverse events caused by gene transfer were detected in 7 out of 77 patients (9.09%). Only one patient experienced peripheral edema (1.30%), in contrast to those who had undergone treatment with VEGF. At 12 weeks after gene transfer, combined evaluation of VAS and ischemic ulcer size demonstrated a significant improvement in HGF gene therapy group as compared to the placebo group (P=0.020).
The long-term analysis revealed a sustained decrease in the size of ischemic ulcer in HGF gene therapy group. In addition, VAS score over 50 mm at baseline (total 27 patients) demonstrated a tendency (P=0.059), but not significant enough, to improve VAS score in HGF gene therapy as compared to the placebo group.
The findings indicated that intramuscular injection of naked HGF plasmid tended to improve the resting pain and significantly decreased the size of the ischemic ulcer in the patients with CLI who did not have any alternative therapy, such as endovascular treatment (EVT) or bypass graft surgery. An HGF gene therapy product, CollategeneTM, was recently launched with conditional and time-limited approval in Japan to treat ischemic ulcer in patients with CLI. Further clinical trials would provide new therapeutic options for patients with CLI.
本联合分析使用裸质粒 DNA 编码肝细胞生长因子（HGF）的临床试验数据，旨在证明肌内注射 HGF 基因治疗对严重肢体缺血（CLI）患者的安全性和疗效。
在大阪大学的一项单中心开放试验中，对 22 例 CLI 患者进行了 HGF 基因转移；在一项随机、安慰剂对照、多中心 III 期试验中，39 例患者；在一项多中心开放试验中，10 例伯格病患者；在一项多中心开放试验中，6 例 CLI 患者采用 2 或 3 次 2 或 4mg 裸 HGF 质粒肌内注射。主要终点为初始注射后 12 周时静息疼痛的视觉模拟量表（VAS）评分和伤口愈合情况。在 77 例患者中发现 7 例（9.09%）由基因转移引起的严重不良事件。与接受 VEGF 治疗的患者相比，只有 1 例患者出现外周水肿（1.30%）。基因转移后 12 周时，HGF 基因治疗组的 VAS 和缺血性溃疡大小综合评估显示明显改善，与安慰剂组相比差异有统计学意义（P=0.020）。
长期分析显示 HGF 基因治疗组缺血性溃疡的大小持续减小。此外，基线时 VAS 评分超过 50mm（共 27 例患者）显示出改善趋势（P=0.059），但与安慰剂组相比，HGF 基因治疗组的 VAS 评分改善不显著。
结果表明，对于没有血管内治疗（EVT）或旁路移植手术等替代治疗方法的 CLI 患者，肌内注射裸 HGF 质粒可改善静息疼痛，显著减小缺血性溃疡的面积。HGF 基因治疗产品 CollategeneTM 最近在日本获得有条件和限时批准，用于治疗 CLI 患者的缺血性溃疡。进一步的临床试验将为 CLI 患者提供新的治疗选择。
