PDF(Pubmed)
Abstract：
Autosomal dominant optic atrophy (ADOA), mostly caused by heterozygous OPA1 mutations and characterized by retinal ganglion cell (RGC) loss and optic nerve degeneration, is one of the most common types of inherited optic neuropathies. Previous work using a two-dimensional (2D) differentiation model of induced pluripotent stem cells (iPSCs) has investigated ADOA pathogenesis but failed to agree on the effect of OPA1 mutations on RGC differentiation. Here, we use 3D retinal organoids capable of mimicking in vivo retinal development to resolve the issue. We generated isogenic iPSCs carrying the hotspot OPA1 c.2708_2711delTTAG mutation and found that the mutant variant caused defective initial and terminal differentiation and abnormal electrophysiological properties of organoid-derived RGCs. Moreover, this variant inhibits progenitor proliferation and results in mitochondrial dysfunction. These data demonstrate that retinal organoids coupled with gene editing serve as a powerful tool to definitively identify disease-related phenotypes and provide valuable resources to further investigate ADOA pathogenesis and screen for ADOA therapeutics.
摘要：
常染色体显性视神经萎缩(ADOA),主要由杂合子OPA1突变引起，以视网膜神经节细胞（RGC）丢失和视神经变性为特征，是最常见的遗传性视神经病变之一。先前使用诱导多能干细胞（iPSC）的二维（2D）分化模型的工作已经研究了ADOA的发病机理，但未能就OPA1突变对RGC分化的影响达成一致。这里,我们使用能够模拟体内视网膜发育的3D视网膜类器官来解决问题。我们产生了携带热点OPA1c.2708_2711delTTAG突变的等基因iPSC，并发现该突变体变体引起了类器官衍生的RGC的初始和终末分化缺陷以及异常的电生理特性。此外，该变体抑制祖细胞增殖并导致线粒体功能障碍。这些数据表明，与基因编辑结合的视网膜类器官可作为明确鉴定疾病相关表型的强大工具，并为进一步研究ADOA发病机理和筛选ADOA疗法提供宝贵的资源。
