title: Safety and efficacy of plasmid DNA expressing two isoforms of hepatocyte growth factor in patients with critical limb ischemia.
abstract: VM202, a plasmid DNA that expresses two isoforms of hepatocyte growth factor, may elicit angiogenic effects that could benefit patients with critical limb ischemia (CLI). In a phase 2, double-blind trial in 52 CLI patients, we examined the safety and potential efficacy of intramuscular injections of low-dose (n=21) or high-dose (n=20) VM202 or placebo (n=11) in the affected limb (days 0, 14, 28 and 42). Adverse events and serious adverse events were similar among the groups; no malignancy or proliferative retinopathy was seen. In exploratory efficacy analyses, we found no differences in ankle or toe-brachial index, VAS, VascuQuol or amputation rate among the groups. Complete ulcer healing was significantly better in high-dose (8/13 ulcers; P<0.01) versus placebo (1/9) patients. Clinically meaningful reductions (>50%) in ulcer area occurred in high-dose (9/13 ulcers) and low-dose (19/27) groups versus placebo (1/9; P<0.05 and P<0.005, respectively). At 12 months, significant differences were seen in TcPO2 between the high-dose and placebo groups (47.5 ± 17.8 versus 36.6 ± 24.0 mm Hg, respectively; P<0.05) and in the change from baseline among the groups (P<0.05). These data suggest that VM202 is safe and may provide therapeutic bioactivity in CLI patients.
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Kibbe
authors.affiliation: University of Minnesota Medical School, Minneapolis, MN, USA.
authors.forename: A T
authors.initials: AT
authors.lastname: Hirsch
authors.affiliation: Cardiology P.C. Research, Birmingham, AL, USA.
authors.forename: F O
authors.initials: FO
authors.lastname: Mendelsohn
authors.affiliation: The Methodist Hospital, Houston, TX, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Davies
authors.affiliation: Boston University School of Medicine, Boston, MA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Pham
authors.affiliation: University of Oklahoma HSC, Oklahoma City, OK, USA.
authors.forename: J
authors.initials: J
authors.lastname: Saucedo
authors.affiliation: University of North Carolina School of Medicine, Chapel Hill, NC, USA.
authors.forename: W
authors.initials: W
authors.lastname: Marston
authors.affiliation: Ewha Womans University Medical Center, Seoul, Korea.
authors.forename: W-B
authors.initials: WB
authors.lastname: Pyun
authors.affiliation: Seoul National University Hospital, Seoul, Korea.
authors.forename: S-K
authors.initials: SK
authors.lastname: Min
authors.affiliation: Saint Louis University Hospital, Louis, MO, USA.
authors.forename: B G
authors.initials: BG
authors.lastname: Peterson
authors.affiliation: Jobst Vascular, Toledo, OH, USA.
authors.forename: A
authors.initials: A
authors.lastname: Comerota
authors.affiliation: Yonsei University Severance Cardiovascular Hospital, Seoul, Korea.
authors.forename: D
authors.initials: D
authors.lastname: Choi
authors.affiliation: Vascular & Interventional Specialists of Orange County, Inc., Orange, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Ballard
authors.affiliation: Stem Cell Center, Texas Heart Institute, Houston, TX, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Bartow
authors.affiliation: Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Losordo
authors.affiliation: Columbia University Medical Center, New York, NY, USA.
authors.forename: W
authors.initials: W
authors.lastname: Sherman
authors.affiliation: Boston University School of Medicine, Boston, MA, USA.
authors.forename: V
authors.initials: V
authors.lastname: Driver
authors.affiliation: Stem Cell Center, Texas Heart Institute, Houston, TX, USA.
authors.forename: E C
authors.initials: EC
authors.lastname: Perin
mesh_terms: D000368:Aged; D005121:Extremities / Q000098:blood supply* / Q000293:injuries*; D005260:Female; D005822:Genetic Vectors / Q000009:adverse effects*; D017228:Hepatocyte Growth Factor / Q000009:adverse effects* / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010957:Plasmids / Q000009:adverse effects; D020033:Protein Isoforms / Q000009:adverse effects / Q000235:genetics
chemical_list: D020033:Protein Isoforms; D017228:Hepatocyte Growth Factor