Targeted Intraceptors for Macular Degeneration

黄斑变性的靶向内受体

• 批准号: 10020985
• 负责人: Randon Michael Burr
• 金额: $ 100.25万
• 依托单位: IVEENA DELIVERY SYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020985
• 关键词: Affect; African Green Monkey; Age; Age related macular degeneration; Anatomy; Animal Model; Animals; Antibody Response; Binding; Blindness; Blood Vessels; Body Surface Area; Body Weight; Bruch' s basal membrane structure; Choroid; Choroidal Neovascularization; Chronic; Cicatrix; Clinical Trials; Control Groups; Cost Analysis; Data; Disease; Dose; Drug Kinetics; Economic Burden; Economics; Endoplasmic Reticulum; Extravasation; Eye; Fibrosis; Financial Hardship; Foundations; Funding; Goals; Growth; Hematology; Hemorrhage; Histology; Human; Immune response; Infection; Infusion procedures; Injections; Intravenous; Lasers; Left; Legal Blindness; Lesion; Location; Macular degeneration; Mediator of activation protein; Modeling; Monkeys; Mus; Nature; Oryctolagus cuniculus; Outpatients; Pain; Patients; Peptide Signal Sequences; Periodicity; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Physicians; Plasmids; Play; Production; Provider; RGD (sequence); Retina; Retinal Detachment; Risk; Rodent; Safety; Small Business Innovation Research Grant; Structure of retinal pigment epithelium; Surgeon; System; Testing; Therapeutic; Time; Toxic effect; Traumatic injury; Treatment Efficacy; VEGFA gene; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Vascular Permeabilities; Vision; Visual; Visual Acuity; angiogenesis; base; clinical development; cohort; cost; economic impact; extracellular; follow-up; geographic atrophy; improved; improved outcome; infection risk; intravenous injection; intravitreal injection; lysyl-aspartyl-glutamyl-leucine; mortality; nanoparticle; nanoparticle delivery; nanoparticle drug; neovascular; neovascularization; neurotoxicity; nonhuman primate; novel; novel therapeutics; outcome forecast; receptor; response; systemic toxicity; targeted delivery; targeted treatment; treatment group

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.

项目摘要 与年龄相关的黄斑变性（AMD）是美国失明的主要原因。 到80岁时，人们估计有2500万个peple在全球范围内。 影响10％-15％的AMD患者的AMD是该疾病的快速形式，如果离开，则会发展为失明 没有治疗。 脉络膜新生血管形成（CNV；血管异常的血管生长，从Chroid到您）上皮（RPE） 视网膜）。 在CNV的发作中起关键作用。 给予抗VEGF-a外的抗VEGF药物 实质上改善了近期程序病，但是超过2年治疗的预后很差，稳定 在几项临床试验中，观察到7年随访的视力下降。 地理萎缩是高慢性抗VEGF治疗，而不是在AMD患者中。 一半的眼睛显示出持续的CNV泄漏，纤维化疤痕和/或地理萎缩 接受抗VEGF疗法的患者人数没有实质性的视觉改善，第三名 被治疗的眼睛继续失去视觉和性，并取得了法律失明的进展。 注射患者和实践的经济负担很大，以及出血的潜在风险， 感染，创伤性损伤和视网膜脱离。 策略，可改善视力并阻止CNV，并以可破坏的安全性降低 风险。 使用第1阶段的资金支持，我们确定了静脉内给药的剂量响应和功效 FLT23K在激光诱导的CNV回归小鼠中的内室； 在第二阶段的小鼠中施用了FLT23K内纳米颗粒。 这种AMD疗法在Anon-Human Primate（NHP，非洲绿猴）激光诱导的功效 CNV模型在GLP条件下。 治疗AMD的方法。 在GMP条件下，这对于在1期临床试验中进行测试是可行的 完成以下特定目标： 目的1：建立静脉内管理FLT23K Intraceptor的药代动力学和安全性 使用GLP条件的兔子中的纳米颗粒。 目的2：确定静脉内管理的FLT23K纳米颗粒的功效 非人类灵长类动物中激光诱导的CNV的回归。