title: Use of a constitutively active hypoxia-inducible factor-1alpha transgene as a therapeutic strategy in no-option critical limb ischemia patients: phase I dose-escalation experience.
abstract: BACKGROUND
  Critical limb ischemia, a manifestation of severe peripheral atherosclerosis and compromised lower-extremity blood flow, results in a high rate of limb loss. We hypothesized that adenoviral delivery of a constitutively active form of the transcription factor hypoxia-inducible factor-1alpha (ie, Ad2/HIF-1alpha/VP16 or HIF-1alpha) into the lower extremity of patients with critical limb ischemia would be safe and might result in a durable clinical response.
  
  
  RESULTS
  This phase I dose-escalation program included 2 studies: a randomized, double-blind, placebo-controlled study and an open-label extension study. In total, 34 no-option patients with critical limb ischemia received HIF-1alpha at doses of 1x10(8) to 2x10(11) viral particles. No serious adverse events were attributable to study treatment. Five deaths occurred: 3 in HIF-1alpha and 2 in placebo patients. In the first (randomized) study, 7 of 21 HIF-1alpha patients met treatment failure criteria and had major amputations. Three of the 7 placebo patients rolled over to receive HIF-1alpha in the extension study. No amputations occurred in the 2 highest-dose groups of Ad2/HIF-1alpha/VP16 (1x10(11) and 2x10(11) viral particles). The most common adverse events included peripheral edema, disease progression, and peripheral ischemia. At 1 year, limb status observations in HIF-1alpha patients included complete rest pain resolution in 14 of 32 patients and complete ulcer healing in 5 of 18 patients.
  
  
  CONCLUSIONS
  HIF-1alpha therapy in patients with critical limb ischemia was well tolerated, supporting further, larger, randomized efficacy trials.
authors.affiliation: Section of Vascular Medicine, 473 W 12th Ave, Division of Cardiovascular Medicine, Ohio State University, Columbus, OH 43210-1252, USA. sanjay.rajagopalon@osumc.edu
authors.forename: Sanjay
authors.initials: S
authors.lastname: Rajagopalan
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Olin
authors.forename: Steven
authors.initials: S
authors.lastname: Deitcher
authors.forename: Ann
authors.initials: A
authors.lastname: Pieczek
authors.forename: John
authors.initials: J
authors.lastname: Laird
authors.forename: P Michael
authors.initials: PM
authors.lastname: Grossman
authors.forename: Corey K
authors.initials: CK
authors.lastname: Goldman
authors.forename: Kevin
authors.initials: K
authors.lastname: McEllin
authors.forename: Ralph
authors.initials: R
authors.lastname: Kelly
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chronos
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000671:Amputation, Surgical; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000009:adverse effects / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D007511:Ischemia / Q000150:complications / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000209:etiology; D059408:Pain Management; D016491:Peripheral Vascular Diseases / Q000150:complications / Q000628:therapy*; D010919:Placebos; D019076:Transgenes; D016896:Treatment Outcome; D014456:Ulcer / Q000209:etiology / Q000628:therapy
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010919:Placebos