TY - JOUR
T1 - Use of a constitutively active hypoxia-inducible factor-1α transgene as a therapeutic strategy in no-option critical limb ischemia patients
T2 - Phase I dose-escalation experience
AU - Rajagopalan, Sanjay
AU - Olin, Jeffrey
AU - Deitcher, Steven
AU - Pieczek, Ann
AU - Laird, John
AU - Grossman, P. Michael
AU - Goldman, Corey K.
AU - McEllin, Kevin
AU - Kelly, Ralph
AU - Chronos, Nicolas
PY - 2007/3
Y1 - 2007/3
N2 - 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 to 2×10 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 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-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.
AB - 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 to 2×10 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 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-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.
KW - Angiogenesis
KW - Gene therapy
KW - Growth substances
KW - Hypoxia
KW - Peripheral vascular disease
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U2 - 10.1161/CIRCULATIONAHA.106.607994
DO - 10.1161/CIRCULATIONAHA.106.607994
M3 - Article
C2 - 17309918
AN - SCOPUS:33947727879
VL - 115
SP - 1234
EP - 1243
JO - Circulation
JF - Circulation
SN - 0009-7322
IS - 10
ER -