Subretinal Rather Than Intravitreal Adeno-Associated Virus-Mediated Delivery of a Complement Alternative Pathway Inhibitor Is Effective in a Mouse Model of RPE Damage.
Subretinal Rather Than Intravitreal Adeno-Associated Virus-Mediated Delivery of a Complement Alternative Pathway Inhibitor Is Effective in a Mouse Model of RPE Damage.
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DOI：
10.1167/iovs.62.4.11
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发表时间：
2021-04-01
影响因子：
4.4
通讯作者：
Rohrer B
中科院分区：
文献类型：
--
作者：
Annamalai B;Parsons N;Nicholson C;Obert E;Jones B;Rohrer B
年龄相关性黄斑变性的风险与过度活跃的补体系统有关。尽管学术界和工业界联合尝试开发调节补体应答的治疗剂，特别是在晚期AMD的晚期地图状萎缩形式中，但迄今为止，没有有效的治疗。我们先前已经证明，在烟雾诱导的眼部病理学（SIOP）模型（与干性AMD相似的模型）中的病理学依赖于旁路补体途径的激活，并且旁路途径的新型补体激活位点靶向抑制剂可以通过腺相关病毒（AAV）递送至眼部组织。比较了用于特异性组织靶向的两种不同病毒载体：用于递送至视网膜色素上皮（RPE）的AAV 5-VMD 2-CR2-fH和用于递送至视网膜神经节细胞（RGC）的AAV 2 YF-smCBA-CR2-fH。在SIOP（6个月被动烟雾吸入）中测试功效，评估视觉功能（视动反应）、视网膜结构（光学相干断层扫描）以及RPE和Bruch膜的完整性（电子显微镜）。使用蛋白质化学来评估补体活化、CR2-fH组织分布和CR2-fH跨RPE的转运。发现RPE介导的而不是RGC介导的CR2-fH分泌减少RPE/脉络膜中的SIOP和补体激活。仅在AAV 5-VMD 2-CR2-fH处理后才能证实RPE/脉络膜中CR2-fH的生物利用度，并且鉴定了CR2-fH穿过RPE的低效的三磷酸腺苷依赖性转运。我们的研究结果表明，AMD样病理学的补体抑制是RPE所必需的基础，并支持AAV载体递送至RPE或血视网膜屏障外。
The risk for age-related macular degeneration has been tied to an overactive complement system. Despite combined attempts by academia and industry to develop therapeutics that modulate the complement response, particularly in the late geographic atrophy form of advanced AMD, to date, there is no effective treatment. We have previously demonstrated that pathology in the smoke-induced ocular pathology (SIOP) model, a model with similarities to dry AMD, is dependent on activation of the alternative complement pathway and that a novel complement activation site targeted inhibitor of the alternative pathway can be delivered to ocular tissues via an adeno-associated virus (AAV). Two different viral vectors for specific tissue targeting were compared: AAV5-VMD2-CR2-fH for delivery to the retinal pigment epithelium (RPE) and AAV2YF-smCBA-CR2-fH for delivery to retinal ganglion cells (RGCs). Efficacy was tested in SIOP (6 months of passive smoke inhalation), assessing visual function (optokinetic responses), retinal structure (optical coherence tomography), and integrity of the RPE and Bruch's membrane (electron microscopy). Protein chemistry was used to assess complement activation, CR2-fH tissue distribution, and CR2-fH transport across the RPE. RPE- but not RGC-mediated secretion of CR2-fH was found to reduce SIOP and complement activation in RPE/choroid. Bioavailability of CR2-fH in RPE/choroid could be confirmed only after AAV5-VMD2-CR2-fH treatment, and inefficient, adenosine triphosphate–dependent transport of CR2-fH across the RPE was identified. Our results suggest that complement inhibition for AMD-like pathology is required basal to the RPE and argues in favor of AAV vector delivery to the RPE or outside the blood-retina barrier.
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影响因子：
9
作者：
Clark SJ;Bishop PN
通讯作者：
Bishop PN
影响因子：
3
作者：
Annamalai B;Parsons N;Belhaj M;Brandon C;Potts J;Rohrer B
通讯作者：
Rohrer B
影响因子：
4.4
作者：
Campa, Claudio;Kasman, Ian;Ferrara, Napoleone
通讯作者：
Ferrara, Napoleone
影响因子：
4.4
作者：
Heesterbeek, Thomas J.;Lechanteur, Yara T. E.;Klevering, B. Jeroen
通讯作者：
Klevering, B. Jeroen
影响因子：
4.6
作者：
Armento, Angela;Honisch, Sabina;Ueffing, Marius
通讯作者：
Ueffing, Marius