Published Online
on February 19, 2007

A more recent version of this article appeared on March 13, 2007

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Submitted on December 13, 2005
Accepted on December 18, 2006

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, and 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.

^* To whom correspondence should be addressed. E-mail: sanjay.rajagopalon{at}osumc.edu.

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.

Key words: angiogenesis • gene therapy • growth substances • hypoxia • peripheral vascular disease

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