Local acting Sticky‐trap inhibits vascular endothelial growth factor dependent pathological angiogenesis in the eye

摘要

AbstractCurrent therapeutic antiangiogenic biologics used for the treatment of pathological ocular angiogenesis could have serious side effects due to their interference with normal blood vessel physiology. Here, we report the generation of novel antivascular endothelial growth factor-A (VEGF) biologics, termed VEGF “Sticky-traps,” with unique properties that allow for local inhibition of angiogenesis without detectable systemic side effects. Using genetic and pharmacological approaches, we demonstrated that Sticky-traps could locally inhibit angiogenesis to at least the same extent as the original VEGF-trap that also gains whole-body access. Sticky-traps did not cause systemic effects, as shown by uncompromised wound healing and normal tracheal vessel density. Moreover, if injected intravitreally, recombinant Sticky-trap remained localized to various regions of the eye, such as the inner-limiting membrane and ciliary body, for prolonged time periods, without gaining access either to the photoreceptors/choriocapillaris area or the circulation. These unique pharmacological characteristics of Sticky-trap could allow for safe treatment of pathological angiogenesis in patients with diabetic retinopathy and retinopathy of pre-maturity.SynopsisA locally delivered, bifunctional recombinant “Sticky-trap” comprising a VEGF-trap and a heparin-binding domain (HBD) can prevent aberrant ocular angiogenesis without affecting systemic physiological VEGF-processes.Bifunctional “Sticky-trap” is comprised of VEGF-trap and a carboxy-terminal HBD.Treatment with recombinant Sticky-trap can prevent the development of abnormal ocular angiogenesis.Sticky-trap remains at the site of delivery; thus, it has a local antiangiogenic activity.Sticky-trap applied in the eye does not compromise systemic physiological VEGF-processes, such as wound healing and kidney function.