Cancer Research Lab

Transgene therapy with hypoxia-inducible factor (HIF)-1a is well tolerated in patients with critical limb ischemia, according to the results of a phase I study reported in the February 19th early online issue of Circulation.

HIF-1a has the potential to normalize intracellular oxygen levels by increasing the synthesis of multiple proangiogenic cytokines and genes that facilitate survival of ischemic tissue, the authors explain.

Dr. Sanjay Rajagopalan from Ohio State University, Columbus, Ohio and colleagues investigated the safety of a modified, constitutively active form of HIF-1a (Ad2/HIF-1a/VP16) in patients with advanced atherosclerosis and tissue ischemia.

All but one of the patients treated with HIF-1a experienced adverse events, the authors report, but most events were mild or moderate in severity and not serious.

The time to treatment failure or amputation did not differ significantly between the HIF-1a and placebo groups, the results indicate, but a smaller proportion of HIF-1a patients (7 out of 34) than placebo patients (3 out of 7) met treatment failure criteria.

A similar proportion of treated and placebo patients experienced dependent edema of the lower extremities and injection site reactions, the researchers note, but there was no evidence for promotion of tumor growth, choroidal neovascularization, or new or active proliferative retinopathy.

Fourteen of 32 HIF-1a patients alive at 1 year had complete rest pain resolution, the report indicates, and 5 of 18 had complete ulcer healing.

Clinical improvement did not correlate with improvements in ankle-brachial index or with MR angiography results, the investigators say.

“These data provide encouraging initial evidence of a potentially important therapeutic approach in the treatment of vascular disease without evidence of serious toxicity,” the authors conclude. “Additional, appropriately powered clinical trials are needed to evaluate the safety and efficacy of modified constitutively active forms of HIF-1a in peripheral arterial disease.”