Document Detail

Use of a constitutively active hypoxia-inducible factor-1alpha transgene as a therapeutic strategy in no-option critical limb ischemia patients: phase I dose-escalation experience.
MedLine Citation:
PMID:  17309918     Owner:  NLM     Status:  MEDLINE    
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-1alpha (ie, Ad2/HIF-1alpha/VP16 or HIF-1alpha) 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-1alpha at doses of 1x10(8) to 2x10(11) viral particles. No serious adverse events were attributable to study treatment. Five deaths occurred: 3 in HIF-1alpha and 2 in placebo patients. In the first (randomized) study, 7 of 21 HIF-1alpha patients met treatment failure criteria and had major amputations. Three of the 7 placebo patients rolled over to receive HIF-1alpha in the extension study. No amputations occurred in the 2 highest-dose groups of Ad2/HIF-1alpha/VP16 (1x10(11) and 2x10(11) viral particles). The most common adverse events included peripheral edema, disease progression, and peripheral ischemia. At 1 year, limb status observations in HIF-1alpha patients included complete rest pain resolution in 14 of 32 patients and complete ulcer healing in 5 of 18 patients. CONCLUSIONS: HIF-1alpha therapy in patients with critical limb ischemia was well tolerated, supporting further, larger, randomized efficacy trials.
Sanjay Rajagopalan; Jeffrey Olin; Steven Deitcher; Ann Pieczek; John Laird; P Michael Grossman; Corey K Goldman; Kevin McEllin; Ralph Kelly; Nicolas Chronos
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Publication Detail:
Type:  Clinical Trial, Phase I; Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't     Date:  2007-02-19
Journal Detail:
Title:  Circulation     Volume:  115     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2007 Mar 
Date Detail:
Created Date:  2007-03-13     Completed Date:  2007-03-29     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1234-43     Citation Subset:  AIM; IM    
Section of Vascular Medicine, 473 W 12th Ave, Division of Cardiovascular Medicine, Ohio State University, Columbus, OH 43210-1252, USA.
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MeSH Terms
Adenoviridae / genetics
Aged, 80 and over
Dose-Response Relationship, Drug
Double-Blind Method
Gene Therapy / adverse effects,  methods*
Genetic Vectors / administration & dosage*,  adverse effects,  genetics
Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
Ischemia / complications,  therapy*
Middle Aged
Pain / etiology,  therapy
Peripheral Vascular Diseases / complications,  therapy*
Treatment Outcome
Ulcer / etiology,  therapy
Reg. No./Substance:
0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Placebos
Comment In:
Circulation. 2007 Mar 13;115(10):1180-3   [PMID:  17353455 ]

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