Targeted Intraceptors for Macular Degeneration

项目摘要 视网膜相关性黄斑变性（AMD）是美国失明的主要原因。它影响了超过25%的 80岁的人。据估计，全世界有2500万人患有AMD。新生血管或“湿” 影响10%-15%的AMD患者的AMD是该疾病的快速形式，如果离开， 未经治疗。组织病理学上，该疾病涉及布鲁赫膜和/或视网膜色素的病变 脉络膜新生血管（CNV）;异常血管从脉络膜生长到视网膜上皮（RPE） 视网膜）。血管内皮生长因子（VEGF）是血管生成和血管通透性的调节因子， 在CNV的发病中起关键作用。目前用于湿性AMD的疗法包括每月或每两个月玻璃体内注射 施用在细胞外隔离VEGF-A的抗VEGF药物。该治疗方法 基本上改善了近期预后，但超过2年的治疗预后差，稳定 在几项临床试验中观察到7年随访时视力下降。长期纤维化率& 地图状萎缩在慢性抗VEGF治疗中高于AMD患者的历史队列。更 超过一半的治疗眼显示持续的CNV渗漏、纤维化瘢痕和/或地图状萎缩。显著 许多接受抗VEGF治疗的患者没有经历实质性的视力改善，三分之一的患者没有经历实质性的视力改善。 的治疗眼继续丧失视力并进展为法律的盲。此外，周期性玻璃体内 注射给患者和实践带来了巨大的经济负担以及潜在的出血风险， 感染、外伤和视网膜脱离。我们的目标是开发一种侵入性较小的治疗方法 策略，该策略改善视力并以可接受的安全性特征阻止CNV， 风险 利用第一阶段的资金支持，我们建立了静脉注射的剂量反应和疗效。 Flt 23 k内受体对激光诱导的小鼠CNV消退的影响;并确定静脉注射Flt 23 k的安全性。 在小鼠中施用Flt 23 k内受体纳米颗粒。在第二阶段，我们建议评估兔子的安全性， 这种新的AMD疗法在非人灵长类动物（NHP，非洲绿色猴）激光诱导的AMD中的功效 GLP条件下的CNV模型。我们还将寻求适当的监管批准， 治疗AMD的方法。我们第二阶段项目的影响包括确定一个安全有效的剂量 其对于在GMP条件下生产以在1期临床试验中在人体中测试是可行的。我们将 实现以下具体目标： 目的1：确定静脉注射Flt 23 k内受体的药代动力学和安全性 使用GLP条件在兔中使用纳米颗粒。 目的2：确定静脉内施用的Flt 23 k内受体纳米颗粒对肿瘤细胞增殖的功效。 非人灵长类动物中激光诱导的CNV消退。

Project Summary Age-related Macular Degeneration (AMD) is the leading cause of blindness in US. It affects over 25% of the people by the age 80. An estimated 25 million people are afflicted with AMD worldwide. Neovascular or “wet” AMD, which affects 10%–15% of AMD patients, is a rapid form of the disease and progresses to blindness if left untreated. Histopathologically, the disease involves lesions in the Bruch's membrane and or retinal pigment epithelium (RPE) with choroidal neovascularization (CNV; abnormal blood vessels growth from choroid into the retina). As a mediator of angiogenesis and vascular permeability, vascular endothelial growth factor (VEGF) plays a key role in the onset of CNV. Current therapy for wet AMD consists of monthly or bimonthly intravitreal administration of anti-VEGF drugs that sequester VEGF-A extracellularly. This therapeutic approach substantially improves near-term prognosis, but prognosis beyond 2 years of treatment is poor, with steady decline in visual acuity observed to 7 years of follow-up in several clinical trials. Long-term rates of fibrosis & geographic atrophy are higher with chronic anti-VEGF therapy than in historic cohorts of AMD patients. More than half of treated eyes show ongoing CNV leakage, fibrotic scarring, and/or geographic atrophy. A significant number of patients receiving anti-VEGF therapy do not experience substantial visual improvement, and a third of treated eyes continue to lose visual acuity and progress to legal blindness. Furthermore, periodic intravitreal injections imposes significant economic burdens on patients and practices as well as potential risks of bleeding, infection, traumatic injury, and retinal detachment. Our goal is to develop a less invasive therapeutic strategy, which improves vision and halts CNV with an acceptable safety profile and presents reduced risk. Using Phase 1 funding support, we established the dose response and efficacy of intravenously administered Flt23k intraceptor on regression of laser-induced CNV in mice; and determined the safety of intravenously administered Flt23k intraceptor nanoparticles in mice. In Phase II, we propose to assess safety in rabbits and the efficacy of this novel AMD therapy in a non-human primate (NHP, African green monkeys) laser induced CNV model under GLP conditions. We will also pursue appropriate regulatory approvals for this transformative approach of treating AMD. The impact of our Phase II project includes identifying a safe and efficacious dose that is feasible for manufacturing under GMP conditions to test in humans in a Phase 1 clinical trial. We will accomplish the following specific aims: Aim 1: To establish pharmacokinetics and safety of intravenously administered Flt23k intraceptor nanoparticles in rabbits using GLP conditions. Aim 2: To establish the efficacy of intravenously administered Flt23k intraceptor nanoparticles on regression of laser-induced CNV in non-human primates.