BLR&D Research Career Scientist Award for Dr. Barbel Rohrer

BLR

• 批准号: 10293580
• 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: 2019
• 资助国家: 美国
• 起止时间: 2019-10-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10293580
• 关键词: Affect; Age; Age related macular degeneration; Alternative Complement Pathway; American; Animal Model; Animals; Award; Barbus; Blindness; Book Chapters; Bruch' s basal membrane structure; Buffaloes; Bystander Effect; Caring; Cell Therapy; Cells; Choroid; Choroidal Neovascularization; Clinical; Clinical Trials; Collaborations; Committee Members; Communication; Communication impairment; Complement; Complement 3d Receptors; Complement Activation; Complement Factor D; Complement Factor H; Data; Disease; Disease Progression; Early treatment; Educational process of instructing; Electrophysiology (science); Employee; Environmental Risk Factor; Eye; Faculty; Funding; Future; Generations; Genetic Polymorphism; Genetic Risk; Genetic study; Goals; Grant; Hematopoietic stem cells; Histologic; Incidence; Inflammation; Intervention; Joints; K-Series Research Career Programs; Knock-in Mouse; Laboratories; Liquid substance; Liver; Location; Macular degeneration; Manuscripts; Medical; Medical Students; Medical center; Mentors; Mission; Modeling; Molecular; Molecular Abnormality; Multiple Sclerosis; Mus; Mutation; Nonexudative age-related macular degeneration; Ocular Pathology; Ophthalmologist; Ophthalmology; Outcome; Participant; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phase II/III Trial; Photoreceptors; Population; Postdoctoral Fellow; Prevalence; Psyche structure; Publications; Publishing; Quality of life; Recovery; Rehabilitation therapy; Research; Research Assistant; Research Personnel; Retina; Retinal Degeneration; Retinal Diseases; Risk; Risk Factors; Role; Rotation; Schools; Science; Scientist; Sensory; Services; Side; Site; Smoke; Smoking; Son; South Carolina; Students; System; Technology; Therapeutic; Time; Tissues; Translating; Traumatic Brain Injury; United States National Institutes of Health; Universities; Veterans; Vision; Vision research; Visit; Work; age related; base; career; cilium biogenesis; clinical application; design; diagnostic strategy; early phase clinical trial; effective therapy; efficacy testing; experience; experimental study; gene therapy; geographic atrophy; high resolution imaging; improved; in vivo imaging; indexing; induced pluripotent stem cell; inhibitor; innovation; member; mouse model; nonhuman primate; novel; novel diagnostics; professor; recruit; sensory system; student mentoring; symposium; tissue repair; treatment strategy; vector; wound healing

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.

年龄相关性黄斑变性 (AMD) 是一种缓慢进展的疾病，涉及遗传异常 和环境的侮辱。它是美国老年人失明的主要原因；以及作为人口 随着年龄的增长，AMD 的患病率持续增长。由于吸烟会增加 AMD 风险，并且 退伍军人吸烟的发生率，受影响的退伍军人比例会更高。可以接受治疗 用于脉络膜新生血管（CNV）；但这些都存在风险，并且只针对 AMD 的一部分人群 患者。早期 AMD 和地图样萎缩（GA；> 85% 的病例）尚无治疗方法，因此 开发早期疾病干预的治疗方法至关重要。虽然机制研究表明 炎症和吸烟是 AMD 的基本组成部分，基因研究表明 补体蛋白的多态性都会增加患 AMD 的风险。最有害的之一 H 因子 (fH) 发生精神突变，H 因子是补体旁路途径 (AP) 的重要抑制剂， 表明对补体驱动的炎症控制不充分是 AMD 的主要危险因素。尽管 动物模型和早期临床试验中的许多令人鼓舞的数据补充了 GA 的治疗方法 迄今为止，尚未在 2/3 期试验中达到临床终点。方法包括阻断补体 因子 C5（末端途径激活剂）或因子 D（fD；AP 激活剂）。这些策略的作用是什么 常见的是大部分药物被浪费在非病理生理学重要的靶分子上； IE。， 体液或组织中的大多数补体成分不参与补体激活，因此 减少补体激活，例如在 RPE、布鲁赫膜 (BrM) 或脉络膜毛细血管 (CC) 处， 必须永久抑制给定补体成分的大部分才能达到所需的效果 效果。此外，补体成分是在眼睛和全身产​​生的，并且许多补体 组件可以穿透BrM；因此，存在几乎无限的补体蛋白库 需要控制。最后，目前还不清楚干性AMD中补体激活的组织是什么；退休- na、RPE、BrM 或 CC。考虑到这些复杂性，我们建议利用我们的初步数据 “可寻址”抑制剂，靶向补体激活位点，无论位置如何（CR2-fH） 通过基因治疗肝脏。我们将确定分娩部位，玻璃体内、视网膜下或脉络膜上，重新 需要获得最佳保护、给药时间窗，并在 AMD 动物模型中确认疗效。 具体来说，载体被设计为最佳地靶向内视网膜、RPE和脉络膜中的细胞，并经过测试 在两种经过验证的小鼠模型（脉络膜新生血管和烟雾诱发的眼部病变）中的功效 奥吉）。最佳载体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， 这项工作旨在将抗补体疗法推向临床应用，其长期目标 开发一种治疗方法以减少 AMD 病例数量并改善退伍军人护理和生活质量。