Complement Factor H-based Therapeutic Strategies in Macular Degeneration

基于补体因子 H 的黄斑变性治疗策略

• 批准号: 10261459
• 负责人: Baerbel Rohrer
• 金额: --
• 依托单位: RALPH H JOHNSON VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10261459
• 关键词: Affect; Age; Age related macular degeneration; Ally; Alternative Complement Pathway; American; Animal Model; Animals; Award; Blindness; Blood Vessels; Blood-Retinal Barrier; Bruch' s basal membrane structure; Caring; Carotenoids; Cell physiology; Cells; Cellular Structures; Choroid; Choroidal Neovascularization; Clinical; Complement; Complement 3d Receptors; Complement Activation; Complement Factor D; Complement Factor H; Complement Inactivators; Data; Development; Diet; Disease; Disease model; Drug Kinetics; Early treatment; Encapsulated; Eye; Fatty acid glycerol esters; Genes; Genetic Polymorphism; Genetic study; Goals; ICAM2 gene; Immunization; Immunologics; In Vitro; Incidence; Inflammation; Intervention; Intravenous; Learning; Lesion; Liquid substance; Liver; Location; Long-Term Effects; Macaca mulatta; Macular degeneration; Modeling; Molecular Abnormality; Mus; Mutation; Nonexudative age-related macular degeneration; Normal Cell; Ocular Pathology; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phase II/III Trial; Population; Prevalence; Prevention; Production; Proteins; Psyche structure; Quality of life; Retina; Retinal Ganglion Cells; Risk; Risk Factors; Route; Side; Site; Smoke; Smoking; Structure; System; Technology; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Toxicology; Vascular Endothelial Growth Factors; Veterans; Viral Vector; Work; adeno-associated viral vector; base; clinical application; cohort; complement system; design; disorder of macula of retina; disorder prevention; early onset; early phase clinical trial; effective therapy; efficacy evaluation; efficacy testing; follow-up; gene therapy; geographic atrophy; improved; in vivo; inhibitor/antagonist; monolayer; mouse model; nonhuman primate; paroxysmal nocturnal hemoglobinuria; subretinal injection; vector

Age-related macular degeneration (AMD) is a slowly progressing disease involving genetic abnormalities and environmental insults. It is the leading cause of blindness for older Americans; and as the population ages, the prevalence of AMD continues to grow. Since smoking increases AMD risk and there is a higher incidence of smoking in veterans, disproportionally more veterans will be affected. Treatments are available for choroidal neovascularization (CNV); but those come with risks and only target a subpopulation of AMD patients. No treatment is available for early AMD and geographic atrophy (GA; >85% of all cases), making it paramount to develop a treatment for early disease intervention. While mechanistic studies have shown that inflammation and smoking are fundamental components of AMD, genetic studies have demonstrated that polymorphisms in complement proteins each increase the risk for developing AMD. One of the most detri- mental mutation occurs in factor H (fH) an essential inhibitor in the complement alternative pathway (AP), suggesting that inadequate control of complement-driven inflammation is a major AMD risk factor. Despite the many encouraging data in animal models and early phase clinical trials, complement therapeutics in GA to date have failed to reach clinical endpoints in phase 2/3 trials. Approaches included blocking complement factor C5 (activator in the terminal pathway) or factor D (fD; AP activator). What these strategies had in common was that most of the drug was wasted on non-pathophysiologically important target molecules; i.e., most complement components in fluids or tissue are not engaged in complement activation and hence to reduce complement activation for example at the RPE, Bruch’s membrane (BrM) or choriocapillaris (CC), the majority of a given complement component has to be permanently inhibited to achieve the desired ef- fect. In addition, complement components are made in the eye and systemically, and many complement components can penetrate BrM; hence an almost unlimited reservoir of complement proteins exists that needs to be controlled. Finally, it is still unclear what is the tissue of complement activation in dry AMD; reti- na, RPE, BrM or CC. Given these complications, we propose to build on our preliminary data utilizing an “addressable” inhibitor that target to sites of complement activation regardless of the location (CR2-fH) de- livered via gene therapy. We will determine the site of delivery, intravitreal, subretinal or suprachoroidal, re- quired for optimal protection, the time window of delivery, and confirm efficacy in animal models of AMD. Specifically, vectors are designed to optimally target cells in the inner retina, RPE and choroid and tested for efficacy in two validated mouse models (choroidal neovascularization and smoke-induced ocular pathol- ogy). The optimal vectors will be confirmed in additional mouse and non-human primate models. Overall, this work is designed to move anti-complement therapy towards clinical application, with the long-term goal of developing a treatment to reduce the number of AMD cases and improve veteran care and quality of life.

与年龄相关的黄斑变性（AMD）是一种缓慢的进展疾病，涉及遗传异常 和环境侮辱。这是老年美国人失明的主要原因。作为人口 年龄，AMD的患病率继续增长。由于吸烟会增加AMD风险，并且有更高的风险 退伍军人吸烟的发生率不成比例地影响更多的退伍军人。可以治疗 用于脉络膜新血管形成（CNV）；但是，这些风险有风险，仅针对AMD的亚群 患者。没有治疗早期AMD和地理萎缩（GA；> 85％的所有情况），使其可获得 为早期疾病干预开发治疗的至关重要。机械研究表明 炎症和吸烟是AMD的基本组成部分，遗传研究表明 补体蛋白质中的多态性增加了发展AMD的风险。最危险的 心理突变发生在因子H（FH）中，是补体替代途径（AP）中的基本抑制剂， 表明对补体驱动的注射的控制不足是AMD危险因素。尽管 动物模型和早期临床试验中的许多令人鼓舞的数据，GA中的补充治疗 迄今为止，在第2/3阶段试验中未能达到临床终点。方法包括阻止完成 因子C5（终端途径中的激活因子）或因子D（FD; AP激活剂）。这些策略的 常见的是，大多数药物都浪费在非病理学上重要的靶标分子上。 IE。， 流体或组织中的大多数竞争成分都不用于完成激活，因此 减少在RPE，BRUCH的膜（BRM）或Choriocapillaris（CC）的完成激活 必须永久抑制给定完成组件的大多数，以实现所需的EF- fect。此外，完成的组件是在眼睛和系统的，许多完成的组件 组件可以穿透BRM；因此，存在几乎无限的补体蛋白质库 需要控制。最后，目前尚不清楚干燥AMD中完成激活的组织是什么？退休 NA，RPE，BRM或CC。鉴于这些并发症，我们建议利用我们的初步数据建立 无论位置（CR2-FH）如何 通过基因治疗生活。我们将确定递送部位，玻璃体内，视网膜下或胸膜上的位置，重新 最佳保护，交付的时间窗口以及确认AMD动物模型中的效率所必需的。 具体而言，矢量设计用于最佳靶向内部视网膜，RPE和脉络膜的细胞并进行了测试。 为了在两个经过验证的小鼠模型（脉络膜新生血管形成和烟雾诱导的眼病原体）中效率 OGY）。最佳矢量将在其他小鼠和非人类灵长类动物模型中得到确认。全面的， 这项工作旨在将抗配合疗法转移到临床应用中，其长期目标 开发一种治疗方法以减少AMD病例的数量并改善退伍军人护理和生活质量。