Zhu Yu, Cao Bowen, Tolone Arianna, Yan Jie, Christensen Gustav, Arango-Gonzalez Blanca, Ueffing Marius, Paquet-Durand François
Cell Death Mechanisms Group, Institute for Ophthalmic Research, University of Tübingen, Tübingen, Germany.
Graduate Training Centre of Neuroscience, University of Tübingen, Tübingen, Germany.
Front Neurosci. 2022 Jul 7;16:938089. doi: 10.3389/fnins.2022.938089. eCollection 2022.
Therapy development for neurodegenerative diseases of the retina constitutes a major unmet medical need, and this may be particularly relevant for inherited diseases of the retina, which are largely untreatable to this day. Therapy development necessitates appropriate models to improve the understanding of the underlying degenerative mechanisms, as well as for the testing and evaluation of novel treatment approaches. This review provides an overview of various model systems used to study retinal neuroprotection. The methods and technologies discussed range from primary retinal cell cultures and cell lines, to retinal organoids and organotypic retinal explants, to the cultivation of whole eyeballs. The advantages and disadvantages of these methods are compared and evaluated, also in view of the 3R principles (i.e., the refinement, reduction, and replacement of live animal testing), to identify suitable alternatives for experimentation. The article further expands on the use of models to test and evaluate neuroprotective treatments and to aid the development of retinal drug delivery systems. Among the pharmacological agents tested and characterized are such that interfere with aberrant cyclic guanosine monophosphate (cGMP) -signaling or such that inhibit the activities of poly (ADP-ribose) polymerase (PARP), histone deacetylases (HDAC), calpain-type proteases, as well as unfolded protein response-related stress. We then introduce nanoparticle-based drug delivery systems and discuss how different systems may be used to assess their efficacy in the treatment of retinal diseases. The summary provides a brief comparison of available models and relates their advantages and limitations to the various experimental requirements, for instance, for studies into disease mechanisms, novel treatments, or retinal toxicity. In many cases, combinations of different models may be required to obtain a comprehensive view of the efficacy of a given retinal neuroprotection approach.
视网膜神经退行性疾病的治疗进展是一个尚未满足的主要医疗需求，这对于遗传性视网膜疾病可能尤为重要，因为时至今日，这些疾病在很大程度上仍无法治疗。治疗进展需要合适的模型来增进对潜在退行性机制的理解，以及用于测试和评估新的治疗方法。本综述概述了用于研究视网膜神经保护的各种模型系统。所讨论的方法和技术范围从原代视网膜细胞培养和细胞系，到视网膜类器官和视网膜组织块，再到全眼球培养。还根据3R原则（即优化、减少和替代活体动物试验）对这些方法的优缺点进行了比较和评估，以确定合适的实验替代方案。本文进一步阐述了如何使用这些模型来测试和评估神经保护治疗方法以及辅助视网膜药物递送系统的开发。在经过测试和表征的药理剂中，有干扰异常环磷酸鸟苷（cGMP）信号传导的药物，或抑制聚（ADP - 核糖）聚合酶（PARP）、组蛋白脱乙酰酶（HDAC）、钙蛋白酶型蛋白酶以及未折叠蛋白反应相关应激活性的药物。然后我们介绍基于纳米颗粒的药物递送系统，并讨论如何使用不同的系统来评估它们在治疗视网膜疾病中的疗效。总结部分简要比较了现有的模型，并将它们的优缺点与各种实验要求相关联，例如，对于疾病机制研究、新治疗方法研究或视网膜毒性研究。在许多情况下，可能需要结合不同的模型才能全面了解给定视网膜神经保护方法的疗效。
