EFFECT OF ANGIOGENIC THERAPIES IN RABBITS WITH PERIPHERAL ARTERY DISEASE

OLEA FERNANDA DANIELA

Mar del Plata

Congreso; Reunión Científica Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2019

Sociedad Argentina de Investigación Clínica

Peripheral artery disease (PAD) is a progressively disabling ailment characterized by decreased arterial blood flow to the lower limbs with no long-lasting effective treatment. Hence, therapeutic angiogenesis induced by gene or cell therapy emerges as an alternative.Fifteen years ago I started a research line, testing different angiogenic therapies in rabbits with experimental PAD. First, I studied the effect of administering a plasmid encoding VEGF165 (pVEGF165) in the ischemic hind limb. This study showed that to increase the density of microvessels and angiographycally visible collaterals, and to decrease pathological lesions it is necessary to repeat the treatment. To extend these effects to the long term without repeating the therapy, we decided to inject adipose stromal cells (ASCs) transfected with pVEGF165, on account that ASCs have been shown to display angiogenic effects through the secretion of angiogenic factors. We observed that both ASCs and ASCs-VEGF groups increased arteriolar density and decreased pathological lesions, but only ASCs-VEGF increased angiographic collaterals. Although these results were positive, the ASCs-VEGF group did not show better results due to the low transfection efficiency of the plasmid vector.In consequence, we recently tested a new strategy consisting of the injection of baculoviral vectors (Bv, which display high transduction efficiency and good safety profile) encoding a mutant form of HIF-1α that is not degraded in the presence of oxygen and therefore allows formation of stable HIF-1 (a transcription factor of several angiogenic molecules, including VEGF). As expected, the Bv mHIF-1α group showed an increase in microvasculature and angiographically visible collaterals with respect to control with no side effects.Given these results, our next project is to produce this therapy under GMP conditions and then design a phase I clinical trial in patients with symptomatic PAD without chances of conventional revascularization.