Retinal ganglion cells (RGCs) serve as the connection between the eye and the brain, with this connection disrupted in glaucoma. Numerous cellular mechanisms have been associated with glaucomatous neurodegeneration, and useful cellular models of glaucoma allow for the precise analysis of degenerative phenotypes. Human pluripotent stem cells (hPSCs) serve as powerful tools for studying human disease, particularly cellular mechanisms underlying neurodegeneration. Thus, efforts focused upon hPSCs with an E50K mutation in the Optineurin (OPTN) gene, a leading cause of inherited forms of glaucoma. CRISPR/Cas9 gene editing introduced the OPTN(E50K) mutation into existing lines of hPSCs, as well as generating isogenic controls from patient-derived lines. RGCs differentiated from OPTN(E50K) hPSCs exhibited numerous neurodegenerative deficits, including neurite retraction, autophagy dysfunction, apoptosis, and increased excitability. These results demonstrate the utility of OPTN(E50K) RGCs as an in vitro model of neurodegeneration, with the opportunity to develop novel therapeutic approaches for glaucoma.

视网膜神经节细胞（RGC）充当眼睛和大脑之间的连接，这种连接在青光眼中被破坏。许多细胞机制已经与青光眼神经变性相关，并且有用的青光眼细胞模型允许对变性表型进行精确分析。人类多能干细胞（hPSC）是研究人类疾病（尤其是神经退行性病变的细胞机制）的强大工具。因此，研究的重点是在Optineurin（OPTN）基因中具有E50K突变的hPSC，这是遗传性青光眼形式的主要原因。CRISPR / Cas9基因编辑将OPTN（E50K）突变引入到hPSC的现有品系中，并从患者来源的品系中生成等基因对照。与OPTN（E50K）hPSC分化的RGC表现出许多神经退行性缺陷，包括神经突退缩，自噬功能障碍，细胞凋亡和兴奋性增加。这些结果证明了OPTN（E50K）RGC的实用性变性的体外模型，并有机会开发青光眼的新型治疗方法。