Use of a constitutively active hypoxia-inducible factor-1α transgene as a therapeutic strategy in no-option critical limb ischemia patients: Phase I dose-escalation experience

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

Research output: Contribution to journalArticle

144 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1234-1243
Number of pages10
JournalCirculation
Volume115
Issue number10
DOIs
StatePublished - Mar 2007
Externally publishedYes

Keywords

  • Angiogenesis
  • Gene therapy
  • Growth substances
  • Hypoxia
  • Peripheral vascular disease

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Fingerprint Dive into the research topics of 'Use of a constitutively active hypoxia-inducible factor-1α transgene as a therapeutic strategy in no-option critical limb ischemia patients: Phase I dose-escalation experience'. Together they form a unique fingerprint.

  • Cite this

    Rajagopalan, S., Olin, J., Deitcher, S., Pieczek, A., Laird, J., Grossman, P. M., Goldman, C. K., McEllin, K., Kelly, R., & Chronos, N. (2007). Use of a constitutively active hypoxia-inducible factor-1α transgene as a therapeutic strategy in no-option critical limb ischemia patients: Phase I dose-escalation experience. Circulation, 115(10), 1234-1243. https://doi.org/10.1161/CIRCULATIONAHA.106.607994