Portal de Periódicos da CAPES

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

2007; Lippincott Williams & Wilkins; Volume: 115; Issue: 10 Linguagem: Inglês

10.1161/circulationaha.106.607994

1524-4539

Sanjay Rajagopalan, Jeffrey W. Olin, Steven R. Deitcher, Ann Pieczek, John R. Laird, Paul Grossman, Corey K. Goldman, Kevin McEllin, Ralph A. Kelly, Nicolas Chronos,

Mesenchymal stem cell research

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 1×10 8 to 2×10 11 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 rolled over to receive HIF-1α in the extension study. No amputations occurred in the 2 highest-dose groups of Ad2/HIF-1α/VP16 (1×10 11 and 2×10 11 viral particles). The most common adverse events included peripheral edema, disease progression, and peripheral ischemia. At 1 year, limb status observations in HIF-1α patients included complete rest pain resolution in 14 of 32 patients and complete ulcer healing in 5 of 18 patients. Conclusions— HIF-1α therapy in patients with critical limb ischemia was well tolerated, supporting further, larger, randomized efficacy trials.