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(Circulation. 2007;115:1234-1243.)
© 2007 American Heart Association, Inc.

Genetics

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

Sanjay Rajagopalan, MD; Jeffrey Olin, DO; Steven Deitcher, MD; Ann Pieczek, RN; John Laird, MD; P. Michael Grossman, MD; Corey K. Goldman, MD, PhD; Kevin McEllin, MS; Ralph Kelly, MD; Nicolas Chronos, MD

From Ohio State University, Section of Vascular Medicine (S.R.), Columbus; Mount Sinai School of Medicine (S.R., J.O.), New York, NY; Cleveland Clinic Foundation (S.D.), Cleveland, Ohio; St Elizabeth’s Medical Center, Boston, Mass (A.P.); Washington Hospital Center, Washington, DC (J.L.); University of Michigan, Ann Arbor (P.M.G.); Ochsner Clinic Foundation, New Orleans, La (C.K.G.); Genzyme Corp, Cambridge, Mass (K.M., R.K.); and Atlanta Cardiology Research Institute, P.C., Atlanta, Ga (N.C.). Dr Deitcher is currently at Nuvelo Corp, San Carlos, Calif.

Correspondence to Sanjay Rajagopalan, MD, Section of Vascular Medicine, 473 W 12th Ave, Division of Cardiovascular Medicine, Ohio State University, Columbus, OH 43210-1252. E-mail sanjay.rajagopalon{at}osumc.edu

Received December 13, 2005; accepted December 18, 2006.

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 (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, placebo-controlled study and an open-label extension study. In total, 34 no-option patients with critical limb ischemia received HIF-1 at doses of 1x10⁸ to 2x10¹¹ 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 (1x10¹¹ and 2x10¹¹ 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.

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CLINICAL PERSPECTIVE

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