Leg Ischemia and Aortoiliac Disease

Effect of Hypoxia-Inducible Factor-1α Gene Therapy on Walking Performance in Patients With Intermittent Claudication

Creager MA, Olin JW, Belch JJF, et al (Brigham and Women’s Hosp and Harvard Med School, Boston, MA; Mount Sinai Med Ctr, NY; Univ of Dundee, Scotland, UK; et al) Circulation 124:1765–1773, 2011^§

Abstract

Background

Hypoxia-inducible factor-1α (HIF-1α) is a transcriptional regulatory factor that orchestrates cellular responses to hypoxia. It increases collateral vessel growth and blood flow in models of hind-limb ischemia. This study tested whether intramuscular administration of Ad2/HIF-1α/VP16, an engineered recombinant type 2 adenovirus vector encoding constitutively active HIF-1α, improves walking time in patients with peripheral artery disease and intermittent claudication.

Methods and Results

Two hundred eighty-nine patients with claudication were randomized in a double-blind manner to 1 of 3 doses of Ad2/HIF-1α/VP16 (2×10⁹, 2×10¹⁰, or 2×10¹¹ viral particles) or placebo, administered by 20 intramuscular injections to each leg. Graded treadmill tests were performed at baseline and then 3, 6, and 12 months after treatment. The primary end point was the change in peak walking time from baseline to 6 months. The secondary end point was change in claudication onset time, and tertiary end points included changes in ankle-brachial index and quality-of-life assessments. Median peak walking time increased by 0.82 minutes (interquartile range, −0.05–1.93 minutes) in the placebo group and by 0.82 minutes (interquartile range, −0.07–2.12 minutes), 0.28 minutes (interquartile range, −0.37–1.70 minutes), and 0.78 minutes (interquartile range, −0.02–2.10 minutes) in the HIF-1α 2×10⁹, 2×10¹⁰, and 2×10¹¹ viral particle groups, respectively (P=NS between placebo and each HIF-1α treatment group). There were no significant differences in claudication onset time, ankle-brachial index, or quality-of-life measurements between the placebo and each HIF-1α group.

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