ECT Implants for Factor H Delivery in Models of AMD

描述（由申请人提供）：年龄相关性黄斑变性（AMD）是一种进展缓慢的多因素疾病，涉及遗传异常和环境损害。老年性黄斑变性是导致60岁以上美国人失明的主要原因。随着人口的老龄化，AMD的患病率将继续增长，在75岁时达到最大危险率~30%。目前可用的治疗方法主要集中在疾病的晚期（脉络膜新生血管形成；CNV）；然而，这些药物具有显著的风险，并且仅针对AMD患者亚群。早期或干性AMD（占所有病例的85%）没有治疗方法。因此，我们学习如何早期发现AMD并开发早期疾病预防的治疗方法是至关重要的。虽然机制研究表明炎症和吸烟是两种AMD的基本组成部分，但遗传学研究表明，不同补体蛋白的多态性都增加了AMD的发病风险。其中最有害的突变发生在因子H （CFH）中，它是补体级联反应替代途径（AP）的重要抑制剂。总的来说，有假设认为对补体驱动的炎症控制不足可能是AMD疾病发病的一个主要因素。有趣的是，最近的一项II期临床试验报告了显著的保护作用

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.