A selective angiogenesis blocker to treat retinopathy of prematurity

项目摘要 早产儿视网膜病变（ROP）是儿童视力丧失的主要原因，目前采用激光治疗 治疗或冷冻疗法。然而，这两种治疗都破坏了周边视觉，以挽救中央视觉， 有限的功效，并且不能解决病理性视网膜新生血管形成的根本原因。没有 由于血管内皮生长因子（VEGF）对ROP的治疗至关重要， 在ROP视网膜的生理性和病理性血管生成中，抗VEGF治疗干扰 早产儿的血管生成和视网膜生成，导致不良反应。因此，VEGF抑制剂 有ROP治疗的安全性问题。为了解决这一迫切的未满足的临床需求，我们最近发现， 分泌颗粒蛋白III（Scg 3）作为高度疾病限制性促血管生成因子，其优先结合并 刺激患病血管而不是正常血管的血管生成。这与VEGF相反，VEGF不加区别地 结合并诱导患病和正常血管的血管生成。我们进一步开发了抗Scg 3单克隆抗体， 和人源化抗体（hAbs）以选择性地抑制病理性而非生理性血管生成。的 抗Scg 3治疗转化的关键障碍是Scg 3与ROP的未知临床相关性。之一 确定临床相关性的方法是鉴定未知的Scg 3受体（Scg 3R）并表征 其在ROP血管上的上调。我们假设Scg 3是ROP的一个临床相关的血管生成因子， 因为在疾病状态下Scg 3R显著上调。在目标1中，我们将使用一种新技术， 筛选并鉴定Scg 3R。在目标2中，我们将验证Scg 3R及其与Scg 3的特异性相互作用。在目标3中，我们 证实与健康视网膜血管相比，ROP上的Scg 3R上调。该项目的成功实施 将解开第一个疾病选择性配体-受体对，专门调节病理性，但不 生理性血管生成Scg 3R的鉴定及其在ROP血管中上调的验证将 明确支持抗Scg 3治疗的临床相关性，并促进抗Scg 3治疗的临床转化。 Scg3 hAbs.

Project Summary Retinopathy of prematurity (ROP) is a leading cause of vision loss in children and is currently treated by laser therapy or cryotherapy. However, both treatments destroy the peripheral vision to save the central vision with limited efficacy and do not address the underlying cause of pathological retinal neovascularization. There is no approved drug therapy for ROP in the U.S. Because vascular endothelial growth factor (VEGF) is critical to both physiological and pathological angiogenesis in ROP retinas, anti-VEGF therapy interferes with vasculogenesis and retinogenesis in premature infants, leading to adverse effects. As a result, VEGF inhibitors have safety concerns for ROP therapy. To address this urgent unmet clinical need, we recently discovered secretogranin III (Scg3) as a highly disease-restricted pro-angiogenic factor that preferentially binds to and stimulates angiogenesis of diseased but not normal vessels. This is in contrast to VEGF which indiscriminately binds to and induces angiogenesis of both diseased and normal vessels. We further developed anti-Scg3 mAbs and humanized antibodies (hAbs) to selectively inhibit pathological but not physiological angiogenesis. The critical barrier for the translation of anti-Scg3 therapy is the unknown clinical relevance of Scg3 to ROP. One of the approaches to define the clinical relevance is to identify the unknown Scg3 receptor (Scg3R) and characterize its upregulation on ROP vessels. We hypothesize that Scg3 is a clinically relevant angiogenic factor to ROP because of the marked upregulation of Scg3R in the disease condition. In Aim 1, we will use a new technique to screen and identify Scg3R. In Aim 2, we will verify Scg3R and its specific interaction with Scg3. In Aim 3, we will confirm Scg3R upregulation on ROP vs. healthy retinal vessels. The successful implementation of this project will unravel the first disease-selective ligand-receptor pair to exclusively regulate pathological but not physiological angiogenesis. Identification of Scg3R and validation of its upregulation on ROP vessels will unambiguously support the clinical relevance of anti-Scg3 therapy and facilitate the clinical translation of anti- Scg3 hAbs.