Aier School of Ophthalmology, Central South University, Changsha, Hunan, China.
Aier Eye Institute, Changsha, Hunan, China.
Stem Cell Res Ther. 2024 May 31;15(1):152. doi: 10.1186/s13287-024-03767-4.
X-linked juvenile retinoschisis (XLRS) is an inherited disease caused by RS1 gene mutation, which leads to retinal splitting and visual impairment. The mechanism of RS1-associated retinal degeneration is not fully understood. Besides, animal models of XLRS have limitations in the study of XLRS. Here, we used human induced pluripotent stem cell (hiPSC)-derived retinal organoids (ROs) to investigate the disease mechanisms and potential treatments for XLRS.
hiPSCs reprogrammed from peripheral blood mononuclear cells of two RS1 mutant (E72K) XLRS patients were differentiated into ROs. Subsequently, we explored whether RS1 mutation could affect RO development and explore the effectiveness of RS1 gene augmentation therapy.
ROs derived from RS1 (E72K) mutation hiPSCs exhibited a developmental delay in the photoreceptor, retinoschisin (RS1) deficiency, and altered spontaneous activity compared with control ROs. Furthermore, the delays in development were associated with decreased expression of rod-specific precursor markers (NRL) and photoreceptor-specific markers (RCVRN). Adeno-associated virus (AAV)-mediated gene augmentation with RS1 at the photoreceptor immature stage rescued the rod photoreceptor developmental delay in ROs with the RS1 (E72K) mutation.
The RS1 (E72K) mutation results in the photoreceptor development delay in ROs and can be partially rescued by the RS1 gene augmentation therapy.
X 连锁青年性视网膜劈裂症（XLRS）是一种由 RS1 基因突变引起的遗传性疾病，导致视网膜分裂和视力障碍。RS1 相关视网膜变性的机制尚未完全阐明。此外，XLRS 的动物模型在 XLRS 的研究中有其局限性。在这里，我们使用人诱导多能干细胞（hiPSC）衍生的视网膜类器官（RO）来研究 XLRS 的发病机制和潜在治疗方法。
从两名 RS1 突变（E72K）XLRS 患者的外周血单核细胞中重编程的 hiPSC 分化为 RO。随后，我们探讨了 RS1 突变是否会影响 RO 的发育，并探索了 RS1 基因增强治疗的效果。
源自 RS1（E72K）突变 hiPSC 的 RO 在感光细胞、视蛋白（RS1）缺乏和自发活动改变方面表现出发育迟缓，与对照 RO 相比。此外，发育迟缓与杆状细胞特异性前体标志物（NRL）和光感受器特异性标志物（RCVRN）的表达减少有关。在感光细胞未成熟阶段，腺相关病毒（AAV）介导的 RS1 基因增强治疗挽救了携带 RS1（E72K）突变的 RO 中的杆状光感受器发育迟缓。
RS1（E72K）突变导致 RO 中的感光细胞发育迟缓，RS1 基因增强治疗可部分挽救。
