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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.
Circulation. 2007 Mar 13; 115(10):1234-43.Circ

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-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.

Authors+Show Affiliations

Section of Vascular Medicine, 473 W 12th Ave, Division of Cardiovascular Medicine, Ohio State University, Columbus, OH 43210-1252, USA. sanjay.rajagopalon@osumc.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

17309918

Citation

Rajagopalan, Sanjay, et al. "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." Circulation, vol. 115, no. 10, 2007, pp. 1234-43.
Rajagopalan S, Olin J, Deitcher S, et al. 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. Circulation. 2007;115(10):1234-43.
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-1alpha transgene as a therapeutic strategy in no-option critical limb ischemia patients: phase I dose-escalation experience. Circulation, 115(10), 1234-43.
Rajagopalan S, et al. 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. Circulation. 2007 Mar 13;115(10):1234-43. PubMed PMID: 17309918.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Rajagopalan,Sanjay, AU - Olin,Jeffrey, AU - Deitcher,Steven, AU - Pieczek,Ann, AU - Laird,John, AU - Grossman,P Michael, AU - Goldman,Corey K, AU - McEllin,Kevin, AU - Kelly,Ralph, AU - Chronos,Nicolas, Y1 - 2007/02/19/ PY - 2007/2/21/pubmed PY - 2007/3/30/medline PY - 2007/2/21/entrez SP - 1234 EP - 43 JF - Circulation JO - Circulation VL - 115 IS - 10 N2 - 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. SN - 1524-4539 UR - https://www.unboundmedicine.com/medline/citation/17309918/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_ L2 - http://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.106.607994?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -