Complement Factor H-based Therapeutic Strategies in Macular Degeneration

描述（由申请人提供）： 视网膜相关性黄斑变性（AMD）是一种涉及遗传因素和环境损伤的缓慢进展的多因素疾病。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。由于吸烟显著增加了AMD的风险，并且退伍军人中吸烟的发生率比一般美国成年平民高20%，因此VA系统将不得不为可能高达700万或更多的AMD病例提供护理。目前可用的治疗集中在疾病的晚期（脉络膜新生血管; 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AMD没有治疗方法（>85%的病例）。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。虽然机械研究已经表明炎症和吸烟是两种形式的AMD的基本组成部分，但遗传研究已经证明，不同补体蛋白中的多态性各自增加发展AMD的风险。最有害的突变之一发生在因子H（fH）中，其是补体级联的旁路途径（AP）中的必需抑制剂。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。最近的临床试验（Genentech; lampalizumab阻断AP的激活剂）支持AP是AMD中的关键靶标的假设。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和激光诱导的CNV。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特异性靶向补体激活位点。CR2结构域确保靶向膜，而不依赖于CFH中存在的含有一些基因突变的内源性配体结合结构域。我们已经证明了使用CR2-fH在体外和体内减少AP依赖性病理学的功效。基于蛋白质的疗法的局限性之一是递送。对于短期治疗，玻璃体内注射用于长期治疗，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：使用预防性和治疗性应用的AAV载体疗法递送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，长期递送替代途径抑制剂CFH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 ab- normalities 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. Since smoking significantly increases the risk of AMD and there is a 20% higher incidence of smoking in veterans than in the general U.S. adult civilian population, the VA system will have to provide care for poten- tially up to 7 millio or more AMD cases. Current available treatments focus on the late stage of the disease (choroidal neovascularization; CNV); however, those come with significant risks and only target subpopulations of AMD patients. No treatment is available for early 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 mech- anistic 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 (fH) an essential inhibitor in the alternative pathway (AP) of the complement cascade. Overall, it has been hypothesized that inadequate con- trol of complement-driven inflammation may be a major factor in disease pathogenesis in AMD. A recent clini- cal trial (Genentech; lampalizumab blocking an activator of the AP), supports the hypothesis that the AP is a critical target in AMD. We have established that complement, and in particular AP activity is involved in differ- ent mouse models of AMD, including smoke-induced ocular pathology and laser-induced CNV. 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. The CR2 domain ensures targeting to membranes without relying on the endogenous ligand-binding domains present in CFH that harbor some of the genetic mutations. We have demonstrated efficacy in vitro and in vivo for reducing AP-dependent pathology using CR2-fH. 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 strat- egies in models of AMD: delivery of CR2-fH using AAV vector therapy using both preventative and therapeutic applications. Here we will be guided by our overall hypothesis that pathologic activation of the AP of comple- ment injures the RPE, and ultimately leads to the development of AMD. We further hypothesize that long-term delivery of the alternative pathway inhibitor CFH will provide an effective therapy for AMD.