McDonald Andrew, Wijnholds Jan
Department of Ophthalmology, Leiden University Medical Center (LUMC), 2333 ZC Leiden, The Netherlands.
Netherlands Institute of Neuroscience, Royal Netherlands Academy of Arts and Sciences (KNAW), 1105 BA Amsterdam, The Netherlands.
Int J Mol Sci. 2024 Mar 1;25(5):2887. doi: 10.3390/ijms25052887.
The human photoreceptor function is dependent on a highly specialised cilium. Perturbation of cilial function can often lead to death of the photoreceptor and loss of vision. Retinal ciliopathies are a genetically diverse range of inherited retinal disorders affecting aspects of the photoreceptor cilium. Despite advances in the understanding of retinal ciliopathies utilising animal disease models, they can often lack the ability to accurately mimic the observed patient phenotype, possibly due to structural and functional deviations from the human retina. Human-induced pluripotent stem cells (hiPSCs) can be utilised to generate an alternative disease model, the 3D retinal organoid, which contains all major retinal cell types including photoreceptors complete with cilial structures. These retinal organoids facilitate the study of disease mechanisms and potential therapies in a human-derived system. Three-dimensional retinal organoids are still a developing technology, and despite impressive progress, several limitations remain. This review will discuss the state of hiPSC-derived retinal organoid technology for accurately modelling prominent retinal ciliopathies related to genes, including , , , and . Additionally, we will discuss the development of novel gene therapy approaches targeting retinal ciliopathies, including the delivery of large genes and gene-editing techniques.
人类光感受器功能依赖于高度特化的纤毛。纤毛功能的紊乱通常会导致光感受器死亡和视力丧失。视网膜纤毛病是一系列遗传异质性的遗传性视网膜疾病，影响光感受器纤毛的各个方面。尽管利用动物疾病模型在理解视网膜纤毛病方面取得了进展，但它们往往缺乏准确模拟观察到的患者表型的能力，这可能是由于与人类视网膜存在结构和功能上的差异。人类诱导多能干细胞（hiPSC）可用于生成另一种疾病模型，即三维视网膜类器官，它包含所有主要的视网膜细胞类型，包括具有纤毛结构的光感受器。这些视网膜类器官有助于在源自人类的系统中研究疾病机制和潜在疗法。三维视网膜类器官仍是一项正在发展的技术，尽管取得了令人瞩目的进展，但仍存在一些局限性。本综述将讨论用于准确模拟与 、 、 和 等基因相关的主要视网膜纤毛病的 hiPSC 衍生视网膜类器官技术的现状。此外，我们将讨论针对视网膜纤毛病的新型基因治疗方法的发展，包括大基因的递送和基因编辑技术。
