Effect of hypoxia-inducible factor-1α gene therapy on walking performance in patients with intermittent claudication

Mark A. Creager, Jeffrey W. Olin, Jill J F Belch, Gregory (Greg) Moneta, Timothy D. Henry, Sanjay Rajagopalan, Brian H. Annex, William R. Hiatt

    Research output: Contribution to journalArticle

    73 Citations (Scopus)

    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 (2×10, 2×10, or 2×10 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 2×10, 2×10, and 2×10 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. CONCLUSIONS-: Gene therapy with intramuscular administration of Ad2/HIF-1α/VP16 is not an effective treatment for patients with intermittent claudication.

    Original languageEnglish (US)
    Pages (from-to)1765-1773
    Number of pages9
    JournalCirculation
    Volume124
    Issue number16
    DOIs
    StatePublished - Oct 18 2011

    Fingerprint

    Hypoxia-Inducible Factor 1
    Intermittent Claudication
    Genetic Therapy
    Walking
    Placebos
    Ankle Brachial Index
    Virion
    Quality of Life
    Peripheral Arterial Disease
    Intramuscular Injections
    Exercise Test
    Adenoviridae
    Blood Vessels
    Leg
    Therapeutics
    Ischemia
    Extremities

    ASJC Scopus subject areas

    • Physiology (medical)
    • Cardiology and Cardiovascular Medicine

    Cite this

    Effect of hypoxia-inducible factor-1α gene therapy on walking performance in patients with intermittent claudication. / Creager, Mark A.; Olin, Jeffrey W.; Belch, Jill J F; Moneta, Gregory (Greg); Henry, Timothy D.; Rajagopalan, Sanjay; Annex, Brian H.; Hiatt, William R.

    In: Circulation, Vol. 124, No. 16, 18.10.2011, p. 1765-1773.

    Research output: Contribution to journalArticle

    Creager, MA, Olin, JW, Belch, JJF, Moneta, GG, Henry, TD, Rajagopalan, S, Annex, BH & Hiatt, WR 2011, 'Effect of hypoxia-inducible factor-1α gene therapy on walking performance in patients with intermittent claudication', Circulation, vol. 124, no. 16, pp. 1765-1773. https://doi.org/10.1161/CIRCULATIONAHA.110.009407
    Creager, Mark A. ; Olin, Jeffrey W. ; Belch, Jill J F ; Moneta, Gregory (Greg) ; Henry, Timothy D. ; Rajagopalan, Sanjay ; Annex, Brian H. ; Hiatt, William R. / Effect of hypoxia-inducible factor-1α gene therapy on walking performance in patients with intermittent claudication. In: Circulation. 2011 ; Vol. 124, No. 16. pp. 1765-1773.
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    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 (2×10, 2×10, or 2×10 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 2×10, 2×10, and 2×10 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. CONCLUSIONS-: Gene therapy with intramuscular administration of Ad2/HIF-1α/VP16 is not an effective treatment for patients with intermittent claudication.",
    author = "Creager, {Mark A.} and Olin, {Jeffrey W.} and Belch, {Jill J F} and Moneta, {Gregory (Greg)} and Henry, {Timothy D.} and Sanjay Rajagopalan and Annex, {Brian H.} and Hiatt, {William R.}",
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    AU - Creager, Mark A.

    AU - Olin, Jeffrey W.

    AU - Belch, Jill J F

    AU - Moneta, Gregory (Greg)

    AU - Henry, Timothy D.

    AU - Rajagopalan, Sanjay

    AU - Annex, Brian H.

    AU - Hiatt, William R.

    PY - 2011/10/18

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    N2 - 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 (2×10, 2×10, or 2×10 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 2×10, 2×10, and 2×10 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. CONCLUSIONS-: Gene therapy with intramuscular administration of Ad2/HIF-1α/VP16 is not an effective treatment for patients with intermittent claudication.

    AB - 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 (2×10, 2×10, or 2×10 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 2×10, 2×10, and 2×10 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. CONCLUSIONS-: Gene therapy with intramuscular administration of Ad2/HIF-1α/VP16 is not an effective treatment for patients with intermittent claudication.

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