Complement Factor H-based Therapeutic Strategies in Macular Degeneration

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侮辱。老年性黄斑变性是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~30%的最大风险比率。由于吸烟大大增加了患AMD的风险，而且退伍军人的吸烟率比普通美国成年平民高出20%，退伍军人管理局系统将不得不为多达700万或更多的AMD病例提供护理。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；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(占所有病例的85%)。因此，我们学习如何及早发现AMD并开发能够及早预防疾病的治疗方法是至关重要的。虽然机械学研究表明炎症和吸烟是这两种形式AMD的基本成分，但遗传学研究表明，不同补体蛋白的多态性都会增加AMD的风险。最有害的突变之一发生在H因子(Fh)中，这是补体级联的替代途径(AP)中的一种基本抑制因子。总体而言，补体驱动的炎症控制不足可能是AMD发病机制中的一个主要因素。最近的一项临床试验(Genentech；lampalizumab阻断AP的激活物)支持AP是AMD的关键靶点的假设。我们已经证实，补体，特别是AP活性参与了AMD的不同小鼠模型，包括烟雾诱导的眼部病理和激光诱导的CNV。最后，我们产生了一个有针对性的CFH，CR2-FH。CR2-FH利用补体受体2结构域将因子H特异性地靶向补体激活的部位。CR2结构域确保靶向到膜，而不依赖于CFH中存在的内源性配体结合结构域，这些结构域包含一些基因突变。我们已经在体外和体内证明了使用CR2-FH减少AP依赖的病理的有效性。以蛋白质为基础的疗法的局限性之一是交付。对于短期治疗，长期治疗采用玻璃体内注射，需要探索其他途径。在这里，我们希望在AMD模型中测试两种治疗策略：使用AAV载体疗法同时使用预防和治疗应用来传递CR2-Fh。在这里，我们将以我们的总体假设为指导，即复合性AP的病理性激活会损害RPE，最终导致AMD的发生。我们进一步假设，长期服用替代途径抑制剂CFH将为AMD提供有效的治疗方法。

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.