Department of Ophthalmology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.
PLoS One. 2011 Apr 28;6(4):e19078. doi: 10.1371/journal.pone.0019078.
Age related macular degeneration (AMD) is the most common cause of blindness amongst the elderly. Approximately 10% of AMD patients suffer from an advanced form of AMD characterized by choroidal neovascularization (CNV). Recent evidence implicates a significant role for complement in the pathogenesis of AMD. Activation of complement terminates in the incorporation of the membrane attack complex (MAC) in biological membranes and subsequent cell lysis. Elevated levels of MAC have been documented on choroidal blood vessels and retinal pigment epithelium (RPE) of AMD patients. CD59 is a naturally occurring membrane bound inhibitor of MAC formation. Previously we have shown that membrane bound human CD59 delivered to the RPE cells of mice via an adenovirus vector can protect those cells from human complement mediated lysis ex vivo. However, application of those observations to choroidal blood vessels are limited because protection from MAC- mediated lysis was restricted only to the cells originally transduced by the vector. Here we demonstrate that subretinal delivery of an adenovirus vector expressing a transgene for a soluble non-membrane binding form of human CD59 can attenuate the formation of laser-induced choroidal neovascularization and murine MAC formation in mice even when the region of vector delivery is distal to the site of laser induced CNV. Furthermore, this same recombinant transgene delivered to the intravitreal space of mice by an adeno-associated virus vector (AAV) can also attenuate laser-induced CNV. To our knowledge, this is the first demonstration of a non-membrane targeting CD59 having biological potency in any animal model of disease in vivo. We propose that the above approaches warrant further exploration as potential approaches for alleviating complement mediated damage to ocular tissues in AMD.
年龄相关性黄斑变性（AMD）是老年人失明的最常见原因。大约 10%的 AMD 患者患有晚期 AMD，其特征是脉络膜新生血管形成（CNV）。最近的证据表明补体在 AMD 的发病机制中起着重要作用。补体的激活以膜攻击复合物（MAC）在生物膜中的掺入以及随后的细胞溶解而告终。AMD 患者的脉络膜血管和视网膜色素上皮（RPE）上有记录到 MAC 水平升高。CD59 是 MAC 形成的天然存在的膜结合抑制剂。以前我们已经表明，通过腺病毒载体递送至 RPE 细胞的膜结合人 CD59 可以保护这些细胞免受人补体介导的体外溶解。然而，这些观察结果在脉络膜血管中的应用受到限制，因为仅对最初被载体转导的细胞具有 MAC 介导的溶解保护。在这里，我们证明，通过腺相关病毒载体（AAV）向视网膜下腔递送表达可溶性非膜结合形式人 CD59 的转基因，可以减轻激光诱导的脉络膜新生血管形成和小鼠 MAC 形成，即使载体递送区域远离激光诱导的 CNV 部位也是如此。此外，通过腺相关病毒载体（AAV）递送至小鼠眼内空间的相同重组转基因也可以减轻激光诱导的 CNV。据我们所知，这是第一个证明非膜靶向 CD59 在任何体内疾病动物模型中具有生物学效力的证明。我们提出，上述方法值得进一步探索，作为减轻 AMD 中眼组织补体介导损伤的潜在方法。
