Use of a constitutively active hypoxia-inducible factor-1 alpha transgene as a therapeutic strategy in no-option critical limb ischemia patients - Phase I dose-escalation experience

Article

关键词: ENDOTHELIAL GROWTH-FACTOR;    PERIPHERAL ARTERIAL-DISEASE;    ADENOASSOCIATED VIRUS;    HINDLIMB ISCHEMIA;    LOWER-EXTREMITY;    GENE-TRANSFER;    DOUBLE-BLIND;    ANGIOGENESIS;    ADENOVIRUS;    HIF-1-ALPHA;   

DOI  :  10.1161/CIRCULATIONAHA.106.607994

来源: SCIE

【 摘 要 】

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-1 alpha (ie, Ad2/HIF-1 alpha/VP16 or HIF-1 alpha) 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-1 alpha at doses of 1 x 10(8) to 2 x 10(11) viral particles. No serious adverse events were attributable to study treatment. Five deaths occurred: 3 in HIF-1 alpha and 2 in placebo patients. In the first (randomized) study, 7 of 21 HIF-1 alpha patients met treatment failure criteria and had major amputations. Three of the 7 placebo patients rolled over to receive HIF-1 alpha in the extension study. No amputations occurred in the 2 highest-dose groups of Ad2/HIF-1 alpha/VP16 (1 x 10(11) and 2 x 10(11) viral particles). The most common adverse events included peripheral edema, disease progression, and peripheral ischemia. At 1 year, limb status observations in HIF-1 alpha patients included complete rest pain resolution in 14 of 32 patients and complete ulcer healing in 5 of 18 patients. Conclusions - HIF-1 alpha therapy in patients with critical limb ischemia was well tolerated, supporting further, larger, randomized efficacy trials.

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