Encapsulated Cell Technology-Based Delivery of a Complement Inhibitor Reduces Choroidal Neovascularization in a Mouse Model.
Encapsulated Cell Technology-Based Delivery of a Complement Inhibitor Reduces Choroidal Neovascularization in a Mouse Model.
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DOI：
10.1167/tvst.7.2.3
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发表时间：
2018-03
影响因子：
3
通讯作者：
Rohrer B
中科院分区：
文献类型：
--
作者：
Annamalai B;Parsons N;Belhaj M;Brandon C;Potts J;Rohrer B
视网膜相关性黄斑变性（AMD）是一种进展缓慢的疾病，风险似乎与过度活跃的补体系统有关。我们以前已经证明，小鼠脉络膜新生血管（CNV）和烟雾诱导的眼部病理可以减少与旁路途径（AP）抑制剂融合蛋白组成的补体受体-2片段连接到抑制结构域的因子H（CR2-fH）时，全身交付。在这里，我们开发了一种实验方法，用基因工程包封的ARPE-19细胞玻璃体内产生CR2-fH。产生ARPE-19细胞以稳定表达CR2或CR2-fH，使用海藻酸钠微囊化，并玻璃体内注射到2个月大的C57 BL/6 J小鼠中。注射后4周用氩激光光凝诱导CNV。使用光学相干断层扫描分析包膜的存在和CNV的进展。通过免疫组织化学在视网膜切片中评价CR2-fH的生物利用度，并通过C3 a ELISA评价其作为AP抑制剂的功效。证实了包裹的ARPE-19细胞分泌CR2-fH或CR2。确定了CR2-fH胶囊减少CNV的有效浓度。生物利用度研究表明，CR2-fH存在于注射小鼠的胶囊和视网膜中，并减少CNV相关的眼部C3 a产生。这些发现表明，当玻璃体内产生AP抑制剂CR2-fH时，可以减少小鼠中的CNV。包封的ARPE-19细胞分泌CR2-fH或其他抗血管生成或促生存因子可能是有用的，作为一个潜在的治疗工具，治疗年龄相关性黄斑变性。
Age-related macular degeneration (AMD) is a slowly progressing disease, and risk appears to be tied to an overactive complement system. We have previously demonstrated that mouse choroidal neovascularization (CNV) and smoke-induced ocular pathology can be reduced with an alternative pathway (AP) inhibitor fusion protein consisting of a complement receptor-2 fragment linked to the inhibitory domain of factor H (CR2-fH) when delivered systemically. Here we developed an experimental approach with genetically engineered encapsulated ARPE-19 cells to produce CR2-fH intravitreally. ARPE-19 cells were generated to stably express CR2 or CR2-fH, microencapsulated using sodium alginate, and injected intravitreally into 2-month-old C57BL/6J mice. CNV was induced using argon laser photocoagulation 4 weeks postinjection. Presence of capsules and progression of CNV was analyzed using optical coherence tomography. Bioavailability of CR2-fH was evaluated in retina sections by immunohistochemistry, and efficacy as an AP inhibitor by C3a ELISA. Secretion of CR2-fH or CR2 from encapsulated ARPE-19 cells was confirmed. An efficacious concentration of CR2-fH capsules to reduce CNV was identified. Bioavailability studies showed that CR2-fH was present in capsules and retinas of injected mice, and reduced CNV-associated ocular C3a production. These findings indicate that the AP inhibitor CR2-fH, when generated intravitreally, can reduce CNV in mouse. Encapsulated ARPE-19 cells secreting CR2-fH or perhaps other antiangiogenic or prosurvival factors might be useful as a potential therapeutic tool to treat age-related macular degeneration.
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DOI：
10.4049/jimmunol.0901826
发表时间：
2009-11-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Banda NK;Levitt B;Glogowska MJ;Thurman JM;Takahashi K;Stahl GL;Tomlinson S;Arend WP;Holers VM
通讯作者：
Holers VM
影响因子：
9
作者：
Clark SJ;Bishop PN
通讯作者：
Bishop PN
靶向补体抑制剂可预防移植后心脏缺血和再灌注损伤，并揭示补体激活替代途径的重要作用
影响因子：
4.4
作者：
Atkinson, Carl;He, Songqing;Tomlinson, Stephen
通讯作者：
Tomlinson, Stephen
影响因子：
4.4
作者：
Courtenay, Monique D.;Cade, William H.;Scott, William K.
通讯作者：
Scott, William K.
影响因子：
2.8
作者：
Moore, Keith;Amos, Jennifer;Potts, Jay D.
通讯作者：
Potts, Jay D.