Use of a Constitutively Active Hypoxia-Inducible Factor-1 Transgene as a Therapeutic Strategy in No-Option Critical Limb Ischemia Patients Phase I Dose-Escalation Experience

Background—Critical limb ischemia, a manifestation of severe peripheral atherosclerosis and compromised lowerextremity 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-1 (ie, Ad2/HIF-1 /VP16 or HIF-1 ) 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, placebocontrolled study and an open-label extension study. In total, 34 no-option patients with critical limb ischemia received HIF-1 at doses of 1 10 to 2 10 viral particles. No serious adverse events were attributable to study treatment. Five deaths occurred: 3 in HIF-1 and 2 in placebo patients. In the first (randomized) study, 7 of 21 HIF-1 patients met treatment failure criteria and had major amputations. Three of the 7 placebo patients rolled over to receive HIF-1 in the extension study. No amputations occurred in the 2 highest-dose groups of Ad2/HIF-1 /VP16 (1 10 and 2 10 viral particles). The most common adverse events included peripheral edema, disease progression, and peripheral ischemia. At 1 year, limb status observations in HIF-1 patients included complete rest pain resolution in 14 of 32 patients and complete ulcer healing in 5 of 18 patients. Conclusions—HIF-1 therapy in patients with critical limb ischemia was well tolerated, supporting further, larger, randomized efficacy trials. (Circulation. 2007;115:1234-1243.)