Long-term follow-up evaluation of results from clinical trial using hepatocyte growth factor gene to treat severe peripheral arterial disease.
OBJECTIVE
As angiogenic growth factors can stimulate the development of collateral arteries, a concept called therapeutic angiogenesis, we performed a phase I/IIa open-label clinical trial using intramuscular injection of naked plasmid DNA encoding hepatocyte growth factor (HGF). We reported long-term evaluation of 2 years after HGF gene therapy in 22 patients with severe peripheral arterial disease.


RESULTS
Twenty-two patients with peripheral arterial disease or Buerger disease staged by Fontaine IIb (n=7), III (n=4), and IV (n=11) were treated with HGF plasmid, either 2 mg or 4 mg ×2. Increase in ankle-branchial pressure index >0.1 was observed in 11 of 14 patients (79 %) at 2 years after gene therapy and in 11 of the 17 patients (65%) at 2 months. Reduction in rest pain (>2 cm in visual analog scale) was observed in 9 of 9 patients (100%) at 2 years and in 8 of 13 (62%) patients at 2 months. At 2 years, 9 of 10 (90%) ischemic ulcers reduced by >25%, accompanied by a reduction in the size of ulcer. Severe complications and adverse effects caused by gene transfer were not detected in any patient throughout the period up to 2 years.


CONCLUSIONS
Overall, the present study demonstrated long-term efficacy of HGF gene therapy up to 2 years. These findings may be cautiously interpreted to indicate that intramuscular injection of naked HGF plasmid is safe, feasible, and can achieve successful improvement of ischemic limbs as sole therapy.
Department of Clinical Gene Therapy, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita 565-0871, Japan.
Hirofumi
H
Makino
Motokuni
M
Aoki
Naotaka
N
Hashiya
Keita
K
Yamasaki
Junya
J
Azuma
Yoshiki
Y
Sawa
Yasufumi
Y
Kaneda
Toshio
T
Ogihara
Ryuichi
R
Morishita
D000328:Adult; D000368:Aged; D000671:Amputation, Surgical / Q000706:statistics & numerical data; D005260:Female; D005500:Follow-Up Studies; D015316:Genetic Therapy / Q000379:methods*; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D015994:Incidence; D007273:Injections, Intramuscular; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D010147:Pain Measurement; D058729:Peripheral Arterial Disease / Q000401:mortality* / Q000628:therapy*; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D015996:Survival Rate; D013919:Thromboangiitis Obliterans / Q000401:mortality / Q000628:therapy; D016896:Treatment Outcome
D017228:Hepatocyte Growth Factor