A non membrane-targeted human soluble CD59 attenuates choroidal neovascularization in a model of age related macular degeneration.
A non membrane-targeted human soluble CD59 attenuates choroidal neovascularization in a model of age related macular degeneration.
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DOI：
10.1371/journal.pone.0019078
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发表时间：
2011-04-28
期刊：
影响因子：
3.7
通讯作者：
Kumar-Singh R
中科院分区：
文献类型：
--
作者：
Cashman SM;Ramo K;Kumar-Singh R
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患者患有以脉络膜新生血管形成（CNV）为特征的晚期AMD。近期证据表明补体在AMD的发病机制中起重要作用。补体的激活最终导致膜攻击复合物（MAC）嵌入生物膜并随后引起细胞裂解。AMD患者的脉络膜血管和视网膜色素上皮（RPE）中已记录到MAC水平升高。CD59是一种天然存在的抑制MAC形成的膜结合蛋白。我们之前已经表明，通过腺病毒载体将膜结合的人CD59递送至小鼠的RPE细胞，能够在体外保护这些细胞免受人类补体介导的裂解。然而，将这些观察结果应用于脉络膜血管是有限的，因为对MAC介导的裂解的保护仅限于最初被载体转导的细胞。在此我们证明，通过腺病毒载体视网膜下递送表达人CD59的可溶性非膜结合形式的转基因，即使载体递送区域远离激光诱导的CNV部位，也能够减轻小鼠中激光诱导的脉络膜新生血管形成和鼠MAC的形成。此外，通过腺相关病毒载体（AAV）将相同的重组转基因递送至小鼠玻璃体内，也能够减轻激光诱导的CNV。据我们所知，这是首次证明非膜靶向的CD59在任何体内疾病动物模型中具有生物学效力。我们提出，上述方法作为减轻AMD中补体介导的眼组织损伤的潜在方法，值得进一步探索。
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.
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DOI：
10.1073/pnas.0501536102
发表时间：
2005-05-17
影响因子：
11.1
作者：
Hageman, GS;Anderson, DH;Allikmets, R
通讯作者：
Allikmets, R
影响因子：
15.9
作者：
HALPERIN, JA;TARATUSKA, A;NICHOLSONWELLER, A
通讯作者：
NICHOLSONWELLER, A
影响因子：
12.4
作者：
Cashman, Siobhan M.;McCullough, Laura;Kumar-Singh, Rajendra
通讯作者：
Kumar-Singh, Rajendra
影响因子：
4.4
作者：
Bora, Nalini S.;Kaliappan, Sankaranarayanan;Bora, Puran S.
通讯作者：
Bora, Puran S.
影响因子：
45.3
作者：
Chévez-Barrios, P;Chintagumpala, M;Hurwitz, RL
通讯作者：
Hurwitz, RL