title: Phase I/IIa clinical trial of therapeutic angiogenesis using hepatocyte growth factor gene transfer to treat critical limb ischemia.
abstract: OBJECTIVE
  To evaluate the safety and feasibility of intramuscular gene transfer using naked plasmid DNA-encoding hepatocyte growth factor (HGF) and to assess its potential therapeutic benefit in patients with critical limb ischemia.
  
  
  RESULTS
  Gene transfer was performed in 22 patients with critical limb ischemia by intramuscular injection of HGF plasmid, either 2 or 4 mg, 2 times. Safety, ankle-brachial index, resting pain on a 10-cm visual analog scale, wound healing, and walking distance were evaluated before treatment and at 2 months after injection. No serious adverse event caused by gene transfer was detected over a follow-up of 6 months. Of particular importance, no peripheral edema, in contrast to that seen after treatment with vascular endothelial growth factor, was observed. In addition, the systemic HGF protein level did not increase during the study. At 2 months after gene transfer, the mean ± SD ankle-brachial index increased from 0.46 ± 0.08 to 0.59 ± 0.13 (P<0.001), the mean ± SD size of the largest ischemic ulcers decreased from 3.08 ± 1.54 to 2.32 ± 1.88 cm (P=0.007), and the mean ± SD visual analog scale score decreased from 5.92 ± 1.67 to 3.04 ± 2.50 cm (P=0.001). An increase in ankle-brachial index by >0.1, a reduction in ulcer size by >25%, and a reduction in visual analog scale score by >2 cm at 2 months after gene transfer were observed in 11 (64.7%) of 17 limbs, 18 (72%) of 25 ulcers, and 8 (61.5%) of 13 limbs, respectively.
  
  
  CONCLUSIONS
  Intramuscular injection of naked HGF plasmid is safe and feasible and can achieve successful improvement of ischemic limbs as sole therapy.
authors.affiliation: Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita 565-0871, Japan. morishit@cgt.med.osaka-u.ac.jp
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Morishita
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
authors.forename: Motokuni
authors.initials: M
authors.lastname: Aoki
authors.forename: Naotaka
authors.initials: N
authors.lastname: Hashiya
authors.forename: Keita
authors.initials: K
authors.lastname: Yamasaki
authors.forename: Junya
authors.initials: J
authors.lastname: Azuma
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Taniyama
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sawa
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kaneda
authors.forename: Toshio
authors.initials: T
authors.lastname: Ogihara
mesh_terms: D000368:Aged; D055109:Ankle Brachial Index; D016638:Critical Illness; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects; D006439:Hemodynamics; D017228:Hepatocyte Growth Factor / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007273:Injections, Intramuscular; D007511:Ischemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D007564:Japan; D035002:Lower Extremity / Q000098:blood supply*; D008297:Male; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000235:genetics; D010146:Pain / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D010147:Pain Measurement; D011446:Prospective Studies; D020127:Recovery of Function; D013997:Time Factors; D016896:Treatment Outcome; D016138:Walking; D014945:Wound Healing
chemical_list: C066855:HGF protein, human; D017228:Hepatocyte Growth Factor