Combined Analysis of Clinical Data on HGF Gene Therapy to Treat Critical Limb Ischemia in Japan.

OBJECTIVE: 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). METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Blood pool contrast-enhanced MRI detects suppression of microvascular permeability in early postinfarction reperfusion after nicorandil therapy.

Nicorandil is an adenosine triphosphate-sensitive potassium channel opener with a nitrate-like effect. It is approved for clinical use in Europe and Japan as an antianginal drug. The purpose of this investigation was to assess the acute effects of nicorandil therapy on microvascular injury using the blood pool MR contrast medium, NC100150 injection (Clariscan). Microvascular injury was produced in 24 rats using 45 min of coronary occlusion / 3 hr reperfusion. Nicorandil was infused at 15 min of occlusion and during reperfusion. Control animals received a saline solution. MR imaging was used to characterize microvascular permeability, quantify the extent of microvascular injury, LV volume, and wall thickness. Hyperenhancement at 30 min after administration of 0.05 mmol/kg Clariscan mapped the extent of ischemia-induced loss of microvascular integrity. The accumulation of Clariscan in the injured region was significantly suppressed in nicorandil compared to control rats. Nicorandil reduced the extent of microvascular injury from 44 +/- 2% to 18 +/- 2% (P < 0.01) and true infarction size from 29 +/- 2% to 12 +/- 1%. The extent of the hyperenhanced region correlated with the true size of area at risk at autopsy. On spin-echo MRI during end-diastole, nicorandil reduced LV end-diastolic volume and preserved wall thickness in remote myocardium; both parameters are markers of LV dilatation caused by acute infarction (remodeling). In conclusion, blood pool contrast-enhanced MRI has the potential to depict and quantify the extent of microvascular permeability and injury. Nicorandil suppressed microvascular permeability, reduced infarction size, and improved LV function in early postinfarction reperfusion.