Work

883. AAV-2 Based Gene Therapy Using Novel Anti-VEGF Molecules for Inhibition of Angiogenesis in the Eye

Year: 2006

Type: article

Abstract: Vascular endothelial growth factor (VEGF) plays a critical role in pathological neovascularization which is a key component of ocular diseases like wet age-related macular degeneration (AMD) or proliferative diabetic retinopathy (PDR). There are several reports of preclinical and clinical studies that demonstrate that antagonizing VEGF is a potentially useful strategy for treating such disorders. One of the most potent binders of VEGF is the VEGF receptor Flt-1. It has been shown in several publications that Flt-1 domains 2 and 3 are both required for efficient binding and neutralization of VEGF. In the current study we have engineered soluble hybrid forms of Flt-1 that represent novel high-affinity VEGF binders with binding affinities comparable to other known high affinity VEGF binders. The biological activity of these constructs was determined in vitro by the HUVECs proliferation assays, VEGF binding assays and BIAcore analysis. Since adeno-associated virus 2 (AAV2) mediated gene delivery offers a means to achieve local delivery of proteins into the eye we have inserted these novel anti-VEGF molecules into A AV2 vectors. In situ analysis and immunohistochemistry analysis of the mouse eye show that intravitreal administration of AAV2 based vector mediates transduction of retinal ganglion cells. Persistent transgene expression was observed for at least 13 months in the mouse eye following AAV2 mediated delivery and no gross transgene-related toxicities were observed. Two models for ocular angiogenesis were employed to access in vivo efficacy (1) The oxygen-induced retinopathy (OIR) model in mice as a model of retinal angiogenesis and (2) Laser induced choroidal neovasculaization model in mice. Data from both in vivo models suggests that these novel anti-VEGF molecules are potent inhibitors of retinal neovascularization.

Source: Molecular Therapy

DOI: 10.1016/j.ymthe.2006.08.972