在人类iPSC衍生的RPE中,PRPF8突变诱导的缺陷通过腺基编辑来挽救
Xihao Sun1,2,3,4, Yuan Liang2,5, Yuqin Liang1,2,3,4
1Aier Academy of Ophthalmology, Central South University, Changsha, Hunan, China.
Investigative ophthalmology & visual science
|January 14, 2026
概括
在PRPF8中发生的突变会导致视网膜色素表皮缺陷. 腺基编辑 (ABE) 纠正了患者衍生细胞中的这些缺陷,显示了对视网膜色素炎 (RP) 的治疗潜力.
科学领域:
- 眼科医生 眼科 眼科
- 遗传学 遗传学 是一个
- 细胞生物学 细胞生物学
背景情况:
- 前mRNA处理因子8 (PRPF8) 突变与视网膜色素炎 (RP) 相关,视网膜色素炎是一种退行性眼睛疾病.
- 在视网膜色素表皮质 (RPE) 中PRPF8突变的精确病理机制尚不清楚.
研究的目的:
- 为了描述来自PRPF8突变患者的RPE中的细胞和分子表型. iPSCs.
- 评估腺基编辑 (ABE) 在纠正PRPF8突变和逆转RPE异常方面的有效性.
主要方法:
- 产生的诱导多能干细胞 (iPSC) -RPE来自异构PRPF8突变和对照线患者.
- 利用CRISPR/Cas9来创建一个诱导突变的iPSC系.
- 评估了RPE功能 (屏障完整性,极性) 和超结构 (微,色素颗粒).
- 进行RNA测序以分析拼接事件和受影响的途径.
- 应用了ABE来纠正患者iPSC中的PRPF8突变,并将纠正的细胞重新分化为RPE.
主要成果:
- 在PRPF8突变的RPE细胞中,PRPF8的表达减少,屏障功能受损,极性受损.
- 超结构分析揭示了突变RPE中角微和色素颗粒的损失.
- 转录组分析发现了异常拼接,特别是在膜组合和黑色素体通路中.
- 通过ABE纠正,成功恢复了PRPF8的表达,并使RPE结构和功能正常化.
结论:
- 通过拼接异常,PRPF8突变会诱导RPE功能障碍和结构缺陷.
- 在iPSC中对PRPF8突变进行ABE介导的纠正可以扭转这些缺陷.
- 这项研究突出了基因编辑策略在治疗PRPF8相关RP的潜力.
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