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.