title: Safety evaluation of clinical gene therapy using hepatocyte growth factor to treat peripheral arterial disease.
abstract: Therapeutic angiogenesis using angiogenic growth factors is expected to be a new treatment for patients with critical limb ischemia (CLI). Because hepatocyte growth factor (HGF) has potent angiogenic activity, we investigated the safety and efficiency of HGF plasmid DNA in patients with CLI as a prospective open-labeled clinical trial. Intramuscular injection of naked HGF plasmid DNA was performed in ischemic limbs of 6 CLI patients with arteriosclerosis obliterans (n=3) or Buerger disease (n=3) graded as Fontaine III or IV. The primary end points were safety and improvement of ischemic symptoms at 12 weeks after transfection. Severe complications and adverse effects caused by gene transfer were not detected in any patients. Of particular importance, no apparent edema was observed in any patient throughout the trial. In addition, serum HGF concentration was not changed throughout the therapy period in all patients. In contrast, a reduction of pain scale of more than 1 cm in visual analog pain scale was observed in 5 of 6 patients. Increase in ankle pressure index more than 0.1 was observed in 5 of 5 patients. The long diameter of 8 of 11 ischemic ulcers in 4 patients was reduced >25%. Intramuscular injection of naked HGF plasmid is safe, feasible, and can achieve successful improvement of ischemic limbs. Although the present data are conducted to demonstrate the safety as phase I/early phase IIa, the initial clinical outcome with HGF gene transfer seems to indicate usefulness as sole therapy for CLI.
authors.affiliation: Department of Geriatric Medicine, Graduate School of Medicine, Osaka University, Japan. morishit@cgt.med.osaka-u.ac.jp
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Morishita
authors.forename: Motokuni
authors.initials: M
authors.lastname: Aoki
authors.forename: Naotaka
authors.initials: N
authors.lastname: Hashiya
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
authors.forename: Keita
authors.initials: K
authors.lastname: Yamasaki
authors.forename: Junya
authors.initials: J
authors.lastname: Azuma
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sawa
authors.forename: Hikaru
authors.initials: H
authors.lastname: Matsuda
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kaneda
authors.forename: Toshio
authors.initials: T
authors.lastname: Ogihara
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D017228:Hepatocyte Growth Factor / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D006801:Humans; D007273:Injections, Intramuscular; D007866:Leg / Q000098:blood supply; D007871:Leg Ulcer / Q000175:diagnosis / Q000628:therapy; D018810:Magnetic Resonance Angiography; D008297:Male; D008875:Middle Aged; D010147:Pain Measurement; D016491:Peripheral Vascular Diseases / Q000175:diagnosis / Q000628:therapy*; D011446:Prospective Studies; D012039:Regional Blood Flow; D013919:Thromboangiitis Obliterans / Q000145:classification / Q000628:therapy; D016896:Treatment Outcome
chemical_list: D017228:Hepatocyte Growth Factor