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

年龄相关性黄斑变性(AMD)是一种进展缓慢的疾病，涉及遗传异常 以及对环境的侮辱。它是导致美国老年人失明的主要原因； 随着年龄的增长，AMD的患病率继续增长。因为吸烟会增加患AMD的风险，而且 退伍军人吸烟的发生率，不成比例地更多的退伍军人会受到影响。治疗方法是可用的 脉络膜新生血管(CNV)；但这些都有风险，而且只针对AMD的亚群 病人。没有治疗早期AMD和地理萎缩的方法(GA；&GT；所有病例的85%)，使其 派拉蒙开发了一种治疗早期疾病的干预方法。虽然机械论研究表明， 炎症和吸烟是AMD的基本成分，遗传学研究表明 补体蛋白的多态都会增加患AMD的风险。其中最令人震惊的- 精神突变发生在补体替代途径(AP)中必不可少的抑制因子H(Fh)中， 提示对补体驱动的炎症控制不足是AMD的一个主要危险因素。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 到目前为止，在2/3期试验中还没有达到临床终点。方法包括阻断补体 因子C5(末端通路中的激活剂)或因子D(FD；AP激活剂)。这些策略在 常见的是大部分药物被浪费在非病理生理学上重要的靶分子上；即， 体液或组织中的大多数补体成分不参与补体激活，因此 减少补体的激活，例如在RPE、Bruch膜(BRM)或脉络膜毛细血管(CC)， 必须永久地抑制给定补体成分的大部分以实现所需的效果- 完美无瑕。此外，补语成分是在眼睛和系统中制造的，还有许多补语 组分可以穿透BRM；因此，存在几乎无限的补体蛋白储存库 需要加以控制。最后，干性AMD中补体激活的组织是什么仍不清楚； NA、RPE、BRM或CC。考虑到这些复杂性，我们建议以我们的初步数据为基础，利用 以补体激活位点为靶点的可寻址抑制物，与(CR2-FH)去化位置无关。 通过基因疗法得到了肝脏。我们将确定分娩的地点，玻璃体内，视网膜下或脉络膜上，重新- 寻求最佳保护，给药的时间窗口，并在AMD动物模型中确认疗效。 具体地说，载体被设计成最佳地靶向视网膜内层、RPE和脉络膜中的细胞并进行测试 在两种有效的小鼠模型(脉络膜新生血管和烟雾诱导的眼部病变)中的疗效 OGY)。最优载体将在其他小鼠和非人类灵长类动物模型中得到确认。总的来说， 这项工作旨在将抗补体疗法推向临床应用，并有长期目标。 开发一种治疗方法，以减少AMD病例的数量，改善退伍军人护理和生活质量。

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.