ECT Implants for Factor H Delivery in Models of AMD

描述（由申请人提供）：视网膜相关性黄斑变性（AMD）是一种缓慢进展的多因素疾病，涉及遗传异常和环境损伤。 AMD是导致60岁以上美国人失明的主要原因。 随着人口老龄化，AMD的患病率将继续增长，在75岁时达到约30%的最大风险率。 目前可用的治疗集中在疾病的晚期（脉络膜新生血管化; CNV）;然而，这些治疗具有显著的风险并且仅针对AMD患者的亚群。 早期或干性AMD（>85%的病例）没有治疗方法。 因此，至关重要的是，我们要学会如何早期检测AMD，并开发早期疾病预防的治疗方法。 虽然机制研究表明炎症和吸烟是两种形式的AMD的基本组成部分，但遗传研究表明，不同补体蛋白的多态性均增加了发生AMD的风险。 最有害的突变之一发生在补体级联的旁路途径（AP）中的必需抑制剂因子H（CFH）中。 总体而言，已经假设补体驱动的炎症控制不足可能是AMD疾病发病机制的主要因素。 有趣的是，最近的一项II期临床试验报告了显着的保护作用， 针对地图状萎缩的进展，在亚组的患者，使用单克隆抗体补体因子D（lampalizumab），所需的激活剂的AP。 我们已经确定，补体，特别是AP活性参与不同的AMD小鼠模型，包括烟雾诱导的眼部病理学，激光诱导的CNV和超氧化物活性的丧失。 最后，我们生成了一个目标CFH，CR2-fH。 CR2-fH使用补体受体2结构域将因子H特异性靶向至补体活化位点，并且已经在体外和体内证明了减少AP依赖性病理的功效。 基于蛋白质的疗法的局限性之一是递送。 对于短期治疗，使用玻璃体内注射;对于长期治疗，需要探索其他途径。 在此，我们希望在AMD模型中测试两种治疗策略：1）使用AAV载体疗法递送CR2-fH;和2）通过包封细胞技术产生和递送CR2-fH。 在此，我们将以我们的总体假设为指导，即补体AP的病理性激活损伤RPE，并最终导致AMD的发展。 我们进一步假设AP抑制剂CR2-fH的长期递送将为AMD提供有效的治疗。

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is a slowly progressing multifactorial disease involving genetic abnormalities and environmental insults. AMD is the leading cause of blindness for Americans over age sixty. As the population ages, the prevalence of AMD will continue to grow, reaching a maximum risk rate of ~30% at age 75. Current available treatments focus on the late stage of the disease (choroidal neovascular- ization; CNV); however, those come with significant risks and only target subpopulations of AMD patients. No treatment is available for early or dry AMD (>85% of all cases). Thus it is paramount that we learn on how to detect AMD early and develop treatments that allow for early disease prevention. While mechanistic studies have shown that inflammation and smoking are fundamental components of both forms of AMD, genetic studies have demonstrated that polymorphisms in different complement proteins each increase the risk for developing AMD. One of the most detrimental mutations occurs in factor H (CFH) an essential inhibitor in the alternative pathway (AP) of the complement cascade. Overall, it has been hypothesized that inadequate control of complement-driven inflammation may be a major factor in disease pathogenesis in AMD. Of interest, a recent phase II clinical trial reported significant protection against the progression of geographic atrophy in subgroups of patients, using a monoclonal antibody against complement factor D (lampalizumab), a required activator of the AP. We have established that complement, and in particular AP activity is involved in different mouse models of AMD, including smoke-induced ocular pathology, laser-induced CNV and loss of superoxide activity. Finally, we have generated a targetable CFH, CR2-fH. CR2-fH uses the Complement Receptor 2 domain to specifically target factor H to sites of complement activation, and have demonstrated efficacy in vitro and in vivo for reducing AP-dependent pathology. One of the limitations of protein-based therapeutics is delivery. For short-term treatments, intravitreal injections are used; for long-term treatments, other avenues need to be explored. Here we wish to test two therapeutic strategies in models of AMD: 1) delivery of CR2-fH using AAV vector therapy; and 2) production and delivery of CR2-fH by encapsulated cell technology. Here we will be guided by our overall hypothesis that pathologic activation of the AP of complement injures the RPE, and ultimately leads to the development of AMD. We further hypothesize that long-term delivery of the AP inhibitor CR2-fH will provide an effective therapy for AMD.