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Effect of hypoxia-inducible factor-1alpha gene therapy on walking performance in patients with intermittent claudication.
Circulation. 2011 Oct 18; 124(16):1765-73.Circ

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(9), 2×10(10), or 2×10(11) 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(9), 2×10(10), and 2×10(11) 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. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00117650.

Authors+Show Affiliations

Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. mcreager@partners.orgNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21947297

Citation

Creager, Mark A., et al. "Effect of Hypoxia-inducible Factor-1alpha Gene Therapy On Walking Performance in Patients With Intermittent Claudication." Circulation, vol. 124, no. 16, 2011, pp. 1765-73.
Creager MA, Olin JW, Belch JJ, et al. Effect of hypoxia-inducible factor-1alpha gene therapy on walking performance in patients with intermittent claudication. Circulation. 2011;124(16):1765-73.
Creager, M. A., Olin, J. W., Belch, J. J., Moneta, G. L., Henry, T. D., Rajagopalan, S., Annex, B. H., & Hiatt, W. R. (2011). Effect of hypoxia-inducible factor-1alpha gene therapy on walking performance in patients with intermittent claudication. Circulation, 124(16), 1765-73. https://doi.org/10.1161/CIRCULATIONAHA.110.009407
Creager MA, et al. Effect of Hypoxia-inducible Factor-1alpha Gene Therapy On Walking Performance in Patients With Intermittent Claudication. Circulation. 2011 Oct 18;124(16):1765-73. PubMed PMID: 21947297.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Effect of hypoxia-inducible factor-1alpha gene therapy on walking performance in patients with intermittent claudication. AU - Creager,Mark A, AU - Olin,Jeffrey W, AU - Belch,Jill J F, AU - Moneta,Gregory L, AU - Henry,Timothy D, AU - Rajagopalan,Sanjay, AU - Annex,Brian H, AU - Hiatt,William R, Y1 - 2011/09/26/ PY - 2011/9/28/entrez PY - 2011/9/29/pubmed PY - 2012/2/1/medline SP - 1765 EP - 73 JF - Circulation JO - Circulation VL - 124 IS - 16 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(9), 2×10(10), or 2×10(11) 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(9), 2×10(10), and 2×10(11) 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. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00117650. SN - 1524-4539 UR - https://www.unboundmedicine.com/medline/citation/21947297/Effect_of_hypoxia_inducible_factor_1alpha_gene_therapy_on_walking_performance_in_patients_with_intermittent_claudication_ L2 - http://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.110.009407?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -