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

视网膜相关性黄斑变性（AMD）是一种涉及遗传异常的缓慢进展的疾病 环境的侮辱。它是美国老年人失明的主要原因; 随着年龄的增长，AMD的患病率持续增长。由于吸烟会增加AMD的风险， 吸烟在退伍军人中的发病率，更多的退伍军人将受到影响。治疗可用 用于脉络膜新生血管（CNV）;但这些药物具有风险，且仅针对AMD亚群 患者早期AMD和地图样萎缩（GA; >85%的病例）没有治疗方法， 最重要的是开发一种早期疾病干预的治疗方法。虽然机械研究表明， 炎症和吸烟是AMD的基本组成部分，遗传研究表明， 补体蛋白中的多态性各自增加发展AMD的风险。最具破坏性的- 精神突变发生在补体旁路途径（AP）中的必需抑制剂H因子（fH）中， 提示补体驱动的炎症控制不足是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，GA的补充治疗， 迄今为止，在2/3期试验中未能达到临床终点。方法包括封闭补体 因子C5（末端通路激活剂）或因子D（fD; AP激活剂）。这些策略 常见的是大部分药物浪费在非病理生理学重要的靶分子上;即， 体液或组织中的大多数补体成分不参与补体激活， 减少例如RPE、Bruch膜（BrM）或脉络膜毛细血管（CC）处的补体激活， 大部分给定的补体成分必须被永久抑制以实现所需的EF。 完美。此外，补体成分是在眼睛和全身，和许多补充 成分可以穿透BrM;因此，存在几乎无限的补体蛋白库， 需要被控制最后，目前还不清楚干性AMD中补体激活的组织是什么;视网膜病变中的补体激活的组织是什么。 Na、RPE、BrM或CC。考虑到这些复杂性，我们建议在初步数据的基础上， 靶向补体激活位点的“可寻址的”抑制剂，而不管位置（CR2-fH）去- 通过基因疗法来治疗肝脏。我们将确定递送部位，玻璃体内，视网膜下或脉络膜上，再- 为了获得最佳保护、递送时间窗，并在AMD动物模型中确认功效， 具体地，载体被设计为最佳靶向内层视网膜、RPE和脉络膜中的细胞，并被测试 在两种经验证的小鼠模型（脉络膜新生血管和烟雾诱导的眼部病变）中的疗效， ogy）。将在其他小鼠和非人灵长类动物模型中确认最佳载体。总的来说， 这项工作旨在将抗补体治疗推向临床应用，其长期目标是 开发一种治疗方法，以减少AMD病例的数量，改善退伍军人的护理和生活质量。

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.