A Phase 2, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter, Dose-Selection Study of Ad2/Hypoxia Inducible Factor (HIF)-1α/VP16 in Patients With Intermittent Claudication

The purpose of this Phase 2 clinical research study is to examine the safety of an experimental gene transfer agent, Ad2/HIF-1α/VP16, and its ability to stimulate the growth of new blood vessels from existing blood vessels (a process called angiogenesis) in an attempt to improve the flow of blood in the legs of patients with peripheral arterial disease (PAD).
Specifically, this study will enroll patients with severe intermittent claudication (IC) which is the stage of PAD in which a patient's walking ability is severely limited, causing pain in the legs upon exercise due to inadequate blood flow to the muscles of the lower limbs.

Start Date01 Feb 2005

Sponsor / Collaborator

Genzyme Corp.

100 Clinical Results associated with HIF-1 alpha gene therapy(The Johns Hopkins University)

100 Translational Medicine associated with HIF-1 alpha gene therapy(The Johns Hopkins University)

100 Patents (Medical) associated with HIF-1 alpha gene therapy(The Johns Hopkins University)

Literatures (Medical) associated with HIF-1 alpha gene therapy(The Johns Hopkins University)

01 Jan 2013·Current Vascular PharmacologyQ4 · MEDICINE

Angiogenetic Potential of Ad2/Hif-1α/Vp16 after Regional Application in a Preclinical Pig Model of Chronic Ischemia

Q4 · MEDICINE

Article

Author: Thormann, Michael ; Fydanaki, Maria ; El-Aouni, Chiraz ; Wuchrer, Alexander ; Kupatt, Christian ; Thein, Eckart ; Hinkel, Rabea ; Lebherz, Corinna ; Boekstegers, Peter

Hif-1α, a master regulator of ischemia-responsive gene induction, controls pro-angiogenic gene expression of VEGF-A, flt-1, IGF-1 and erythropoietin, rendering its overexpression an attractive tool for therapeutic neovascularization. Utilizing an adenoviral vector system, we investigated the efficacy of selective pressure-regulated venous retroinfusion of an enhanced Hif-1α mutant (Hif-1α/VP16) in a randomized investigator-blinded study.METHODSPigs were subjected to percutaneous implantation of a reduction-stent into the circumflex artery, leading to progressive stenosis and complete occlusion at day 28. Selective pressure-regulated retroinfusion of the great cardiac vein was performed at day 28 for regional delivery of either saline or empty vector or Ad2/Hif-1α/VP16. Collateral growth and global myocardial function were obtained by fluoroscopy, whereas regional blood flow and regional myocardial function were assessed by fluorescent microsphere analysis and sonomicrometry, respectively. Capillary density in the ischemic myocardium was analyzed by PECAM-1 staining.RESULTSCompared to saline and Ad empty vector controls, overexpression of Hif-1α in the ischemic region induced an increase of small (capillary) and large (collateral) vessels, resulting in an improved perfusion of the ischemic myocardium. Concomitantly, an ischemia induced loss of myocardial function (hibernating myocardium) was resolved only after transfection with the Hif 1-α transgene, but not the empty vector or saline control.CONCLUSIONRetroinfusion of Ad2/Hif-1α/VP16, combining a master pro-angiogenic protein with regional myocardial application, may offer an efficient approach to cardiac gene therapy of chronic ischemic cardiomyopathy.

18 Oct 2011·CirculationQ1 · MEDICINE

Effect of Hypoxia-Inducible Factor-1α Gene Therapy on Walking Performance in Patients With Intermittent Claudication

Q1 · MEDICINE

Article

Author: Henry, Timothy D. ; Olin, Jeffrey W. ; Hiatt, William R. ; Rajagopalan, Sanjay ; Belch, Jill J.F. ; Creager, Mark A. ; Moneta, Gregory L. ; Annex, Brian H.

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.

01 May 2009·The Journal of Gene MedicineQ4 · MEDICINE

A hypoxic inducible factor‐1α hybrid enhances collateral development and reduces vascular leakage in diabetic rats

Q4 · MEDICINE

Article

Author: Canwen Jiang ; Zhengyu Luo ; Richard J. Gregory ; Seng H. Cheng ; Karen A. Vincent ; Geoffrey Y. Akita ; Hidetoshi Kajiwara ; Adam J. Belanger ; Seibu Mochizuki ; Akihiro Urabe

AbstractBackgroundDiabetes mellitus is a common comorbidity of atherosclerosis. Hypoxia‐inducible factor‐1 (HIF‐1) is the master regulator of the angiogenic response to hypoxia.MethodsWe studied the effects of adenoviral vectors expressing a constitutively active HIF‐1α hybrid (Ad2/HIF‐1α/VP16) or vascular endothelial growth factor (Ad2/VEGF) on collateral development and vascular leakiness in a diabetic rat model of hindlimb ischemia.ResultsAfter the removal of the right femoral artery, the mRNA levels of VEGF, angiopoietin‐1 and angiopietin‐4 in the calf muscles, as measured by Taqman reverse transcriptase‐polymerase chain reaction, were transiently elevated in Zucker lean (ZL) but not Zucker diabetic fatty (ZDF) rats. The angiographic score, as determined by post‐mortem angiography, was significantly lower in ZDF animals 35 days after surgery compared to their ZL counterparts. In separate animals, intramuscular injection of Ad2/HIF‐1a/VP16 and Ad/2VEGF into the thigh muscles significantly increased the angiographic score and capillary density 21 and 35 days after the injection compared to Ad2/CMVEV (a vector expressing no transgene) or vehicle. After the injection of Ad2/CMVEV or vehicle, the Evans‐blue dye content in the thigh muscles was significantly higher in ZDF rats than their ZL counterparts. Ad2/HIF‐1α/VP16 but not Ad2/VEGF reduced tissue Evans blue dye content.ConclusionsThe endogenous angiogenic response to ischemia was impaired in ZDF rats, possibly due to down‐regulation of angiogenic factors. Ad2/HIF‐1α/VP16 enhanced collateral development and reduced vascular leakage in the ischemic hindlimb of ZDF rats indicating that hybrid HIF‐1α angiogenic therapy may be efficacious for peripheral vascular disease with a diabetic comorbidity. Copyright © 2009 John Wiley & Sons, Ltd.

100 Deals associated with HIF-1 alpha gene therapy(The Johns Hopkins University)

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Indication	Highest Phase	Country/Location	Organization	Date
Atherosclerosis	Phase 2	GB	-	01 Feb 2005
Atherosclerosis	Phase 2	US	-	01 Feb 2005
Atherosclerosis	Phase 2	DE	-	01 Feb 2005
Peripheral Vascular Diseases	Phase 2	DE	-	01 Feb 2005
Peripheral Vascular Diseases	Phase 2	GB	-	01 Feb 2005
Peripheral Vascular Diseases	Phase 2	US	-	01 Feb 2005
Intermittent Claudication	Phase 2	US	Genzyme Corp.	-
Intermittent Claudication	Phase 2	EU	Genzyme Corp.	-
Peripheral Arterial Disease	Phase 2	CN	Shanghai Sunway Biotech Co., Ltd.	-
Peripheral Arterial Disease	Phase 2	-	The Johns Hopkins University	-

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