Sanada Fumihiro, Taniyama Yoshiaki, Kanbara Yasuhiro, Otsu Rei, Ikeda-Iwabu Yuka, Carracedo Miguel, Rakugi Hiromi, Morishita Ryuichi
Osaka University Graduate School of Medicine, Department of Clinical Gene Therapy , Suita, Osaka 565-0871 , Japan.
Expert Opin Biol Ther. 2015 Mar;15(3):381-90. doi: 10.1517/14712598.2015.1007039. Epub 2015 Jan 29.
Despite the remarkable progress of medicine and endovascular procedures for revascularization, patients with critical limb ischemia (CLI) remain at high risk for amputation and often have a low quality of life due to pain and ulcers in the ischemic leg. Thus, a novel strategy for generating new blood vessels in CLI patients without treatment options is vital. Pre-clinical studies and Phase I clinical trials using VEGF and fibroblast growth factor (FGF) demonstrated promising results; however, more rigorous Phase II and III clinical trials failed to demonstrate benefits for CLI patients. Recently, two multicenter, double-blind, placebo-controlled clinical trials in Japan (Phase III) and the USA (Phase II) showed the benefits of hepatocyte growth factor (HGF) gene therapy for CLI patients. Although the number of patients included in these trials was relatively small, these results imply a distinct beneficial function for HGF over other angiogenic growth factors in a clinical setting.
In this review, data from Phase I-III clinical trials of gene therapy for patients with peripheral artery disease (PAD) are examined. In addition, the potential mechanisms behind the success or failure of clinical trials are discussed.
Compared with VEGF and FGF, HGF has a unique molecular effect on inflammation, fibrosis and cell senescence under pathological conditions. These features may explain the clinical benefits of HGF in PAD patients.
尽管医学和血管内血运重建手术取得了显著进展，但严重肢体缺血（CLI）患者截肢风险仍然很高，且由于缺血肢体的疼痛和溃疡，生活质量往往较低。因此，为没有治疗选择的CLI患者开发一种生成新血管的新策略至关重要。使用血管内皮生长因子（VEGF）和成纤维细胞生长因子（FGF）的临床前研究和I期临床试验取得了有前景的结果；然而，更严格的II期和III期临床试验未能证明对CLI患者有益。最近，日本的两项多中心、双盲、安慰剂对照临床试验（III期）和美国的一项试验（II期）显示了肝细胞生长因子（HGF）基因治疗对CLI患者的益处。尽管这些试验纳入的患者数量相对较少，但这些结果表明在临床环境中HGF相对于其他血管生成生长因子具有独特的有益作用。
在本综述中，我们研究了外周动脉疾病（PAD）患者基因治疗I - III期临床试验的数据。此外，还讨论了临床试验成败背后的潜在机制。
与VEGF和FGF相比，HGF在病理条件下对炎症、纤维化和细胞衰老具有独特的分子作用。这些特性可能解释了HGF对PAD患者的临床益处。
