Ralph H. Johnson VA Medical Center, Division of Research, 29401, Charleston, SC, USA,
Adv Exp Med Biol. 2014;801:435-40. doi: 10.1007/978-1-4614-3209-8_55.
Complement activation is associated with age-related macular degeneration (AMD), with the retinal pigment epithelium (RPE) being one of the main target tissues. In AMD, disease severity is correlated with the formation of the membrane attack complex (MAC), the terminal step in the complement cascade, as well as diminished RPE expression of CD59, a membrane-bound regulatory protein of MAC formation. This has prompted the search for therapeutic strategies based on MAC inhibition, and soluble forms of CD59 (sCD59) have been investigated in mouse laser-induced choroidal neovascularization, a model for "wet" AMD. Unlike membrane-bound CD59, sCD59 provides relatively poor cell protection from complement, and different strategies to increase sCD59 activity at the cell membrane level have been investigated. These include increasing the circulatory half-life of sCD59 by the addition of an Fc moiety; increasing the half-life of sCD59 in target tissues by modifying CD59 with a (non-specific) membrane-targeting domain; and by locally overexpressing sCD59 via adenoviral vectors. Finally, a different strategy currently under investigation employs complement receptor (CR)2-mediated targeting of CD59 exclusively to membranes under complement attack. CR2 recognizes long-lasting membrane-bound breakdown activation fragments of complement C3. CR2-CD59 may have greater therapeutic potential than other complement inhibitory approaches, since it can be administered either systemically or locally, it will bind specifically to membranes containing activated complement activation fragments, and dosing can be regulated. Hence, this strategy might offer opportunities for site-specific inhibition of complement in diseases with restricted sites of inflammation such as AMD.
补体激活与年龄相关性黄斑变性（AMD）有关，视网膜色素上皮（RPE）是主要的靶组织之一。在 AMD 中，疾病的严重程度与膜攻击复合物（MAC）的形成相关，MAC 是补体级联反应的终末步骤，以及 RPE 表达的 CD59 减少，CD59 是 MAC 形成的膜结合调节蛋白。这促使人们寻找基于 MAC 抑制的治疗策略，并且已经在小鼠激光诱导脉络膜新生血管化模型中研究了可溶性 CD59（sCD59），该模型模拟了“湿性”AMD。与膜结合的 CD59 不同，sCD59 为细胞提供相对较差的补体保护，并且已经研究了不同的策略来增加细胞膜水平上 sCD59 的活性。这些策略包括通过添加 Fc 部分来增加 sCD59 的循环半衰期；通过用（非特异性）膜靶向结构域修饰 CD59 来增加靶组织中 sCD59 的半衰期；并通过腺病毒载体局部过表达 sCD59。最后，目前正在研究的一种不同策略是通过补体受体（CR）2 介导的靶向作用将 CD59 专门靶向补体攻击下的膜。CR2 识别补体 C3 的持久膜结合的分解激活片段。CR2-CD59 可能比其他补体抑制方法具有更大的治疗潜力，因为它可以全身或局部给药，它将特异性结合含有激活的补体激活片段的膜，并且可以调节剂量。因此，该策略可能为 AMD 等炎症部位受限的疾病提供针对补体的特定部位抑制的机会。
