ECT Implants for Factor H Delivery in Models of AMD

描述(申请人提供)：老年性黄斑变性(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。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。虽然机制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都会增加发生AMD的风险。最有害的突变之一发生在H因子(CFH)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，有人假设，补体驱动的炎症控制不足可能是AMD疾病发病的主要因素。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 使用抗补体因子D(Lampalizumab)的单抗(AP所需的激活剂)来对抗亚组患者的地理萎缩的进展。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，激光诱导的CNV和超氧化物歧化活性的丧失。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部位，并在体外和体内证明了降低AP依赖性病理的有效性。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，使用玻璃体内注射；对于长期治疗，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：1)使用AAV载体疗法输送CR2-Fh；2)通过微囊化细胞技术生产和输送CR2-Fh。在这里，我们将遵循我们的总体假设，即补体AP的病理性激活会损害RPE，并最终导致AMD的发生。我们进一步假设，长期服用AP抑制剂CR2-FH将为AMD提供一种有效的治疗方法。

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.