Use of a Constitutively Active Hypoxia-Inducible Factor-1α Transgene as a Therapeutic Strategy in No-Option Critical Limb Ischemia Patients

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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-1α (ie, Ad2/HIF-1α/VP16 or HIF-1α) into the lower extremity of patients with critical limb ischemia would be safe and might result in a durable clinical response. Methods and 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-1α at doses of 1×108 to 2×1011 viral particles. No serious adverse events were attributable to study treatment. Five deaths occurred: 3 in HIF-1α and 2 in placebo patients. In the first (randomized) study, 7 of 21 HIF-1α patients met treatment failure criteria and had major amputations. Three of the 7 placebo patients ro...