Efficacy of Intravitreal Multi-Characteristic Opsin (MCO-010) Optogenetic Gene Therapy in a Mouse Model of Leber Congenital Amaurosis.

IF 1.9 4区 医学 Q2 OPHTHALMOLOGY Journal of Ocular Pharmacology and Therapeutics Pub Date : 2024-10-23 DOI:10.1089/jop.2024.0084
Adnan Dibas, Subrata Batabyal, Sanghoon Kim, Michael Carlson, Samarendra Mohanty, Najam A Sharif
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Abstract

Purpose: Leber congenital amaurosis (LCA) is a sight-threatening inherited retinal disorder (IRD) caused by numerous genetic mutations. Multi-characteristic opsin (MCO)-based optogenetic therapy allows the recruitment of residual cells of the retina in LCA for alternative vision transduction while being mutation-agnostic. Using rd12 mice, we investigated the in vivo efficacy of an adeno-associated virus2 (AAV2)-transduced ambient light-activatable MCO (MCO-010) containing a metabotropic glutamate receptor-6 bipolar cell-specific promoter/enhancer. Methods: Mice requiring > 40 s to reach and board a dimly lit hidden platform in a water-maze were selected and randomly divided into 2 cohorts. These mice were intravitreally (IVT) injected with either 1.7E9 gene copies/eye of MCO-010 or control AAV2 and re-tested in the water-maze. Spectral-domain optical coherence tomography (SD-OCT), hematoxylin and eosin staining of retinas, and electroretinographic (ERG) studies were also conducted. Results: Safety of MCO-010 in rd12 mice was confirmed by the lack of significant detrimental changes in the mouse behavior, b-wave amplitudes and in retinal thickness. rd12 control mice performed relatively poorly in the water-maze test requiring ≥ 30-60 s to find and board the platform. MCO-010-treated rd12 mice reached the platform much faster than the AAV2-treated rd12 mice, with some mice only requiring < 5 s to achieve this goal (P < 0.01-0.0024). Conclusions: IVT MCO-010 treatment was well tolerated by rd12 mice, and it prevented the decrease in retinal thickness, and preserved ERG parameters. It also significantly improved the vision in rd12 mice relative to control AAV2-injected mice. MCO-010 therefore represents a novel and efficacious optogenetic therapeutic to treat LCA and other IRDs irrespective of the genetic defect(s).

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雷伯先天性失明小鼠模型中的玻璃体内多特征光蛋白(MCO-010)光遗传基因疗法的疗效。
目的:Leber 先天性无视力症(LCA)是一种由多种基因突变引起的危及视力的遗传性视网膜疾病(IRD)。基于多特性视蛋白(MCO)的光遗传疗法可以招募 LCA 患者视网膜上的残余细胞,进行替代性视力传导,同时又与基因突变无关。我们利用 rd12 小鼠研究了腺相关病毒 2(AAV2)转导的环境光激活型 MCO(MCO-010)的体内疗效,该 MCO 含有代谢性谷氨酸受体-6 双极细胞特异性启动子/增强子。方法:选择需要 > 40 秒才能到达并登上水迷宫中光线昏暗的隐藏平台的小鼠,并将其随机分为 2 组。这些小鼠经玻璃体内(IVT)注射 1.7E9 基因拷贝/眼的 MCO-010 或对照 AAV2,并在水迷宫中重新进行测试。此外,还进行了光谱域光学相干断层扫描(SD-OCT)、视网膜苏木精和伊红染色以及视网膜电图(ERG)研究。研究结果rd12对照组小鼠在水迷宫试验中表现相对较差,需要≥30-60秒才能找到并登上平台。经 MCO-010 处理的 rd12 小鼠比经 AAV2 处理的 rd12 小鼠更快到达平台,有些小鼠只需要 < 5 秒就能达到这一目标(P < 0.01-0.0024)。结论Rd12 小鼠对 IVT MCO-010 治疗的耐受性良好,它能防止视网膜厚度的下降,并保留 ERG 参数。与注射 AAV2 的对照组相比,MCO-010 还能明显改善 rd12 小鼠的视力。因此,MCO-010是治疗LCA和其他IRD的一种新颖而有效的光遗传疗法,无论其是否存在遗传缺陷。
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来源期刊
CiteScore
4.60
自引率
4.30%
发文量
72
审稿时长
1 months
期刊介绍: Journal of Ocular Pharmacology and Therapeutics is the only peer-reviewed journal that combines the fields of ophthalmology and pharmacology to enable optimal treatment and prevention of ocular diseases and disorders. The Journal delivers the latest discoveries in the pharmacokinetics and pharmacodynamics of therapeutics for the treatment of ophthalmic disorders. Journal of Ocular Pharmacology and Therapeutics coverage includes: Glaucoma Cataracts Retinal degeneration Ocular infection, trauma, and toxicology Ocular drug delivery and biotransformation Ocular pharmacotherapy/clinical trials Ocular inflammatory and immune disorders Gene and cell-based therapies Ocular metabolic disorders Ocular ischemia and blood flow Proliferative disorders of the eye Eyes on Drug Discovery - written by Gary D. Novack, PhD, featuring the latest updates on drug and device pipeline developments as well as policy/regulatory changes by the FDA.
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