HIF-1 alpha gene therapy(The Johns Hopkins University)

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.

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.

Gene therapy with intramuscular administration of Ad2/HIF-1α/VP16 is not an effective treatment for patients with intermittent claudication.

URL: http://www.clinicaltrials.gov . Unique identifier: NCT00117650.

Diabetes mellitus is a common comorbidity of atherosclerosis. Hypoxia‐inducible factor‐1 (HIF‐1) is the master regulator of the angiogenic response to hypoxia.

We 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.

After 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.

The 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.