Institute for Vision Research, Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, United States.
Institute for Vision Research, Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, IA, United States; Department of Biochemical Engineering, University of Iowa, Iowa City, IA, United States.
Prog Retin Eye Res. 2018 Jul;65:28-49. doi: 10.1016/j.preteyeres.2018.03.003. Epub 2018 Mar 22.
Gene correction is a valuable strategy for treating inherited retinal degenerative diseases, a major cause of irreversible blindness worldwide. Single gene defects cause the majority of these retinal dystrophies. Gene augmentation holds great promise if delivered early in the course of the disease, however, many patients carry mutations in genes too large to be packaged into adeno-associated viral vectors and some, when overexpressed via heterologous promoters, induce retinal toxicity. In addition to the aforementioned challenges, some patients have sustained significant photoreceptor cell loss at the time of diagnosis, rendering gene replacement therapy insufficient to treat the disease. These patients will require cell replacement to restore useful vision. Fortunately, the advent of induced pluripotent stem cell and CRISPR-Cas9 gene editing technologies affords researchers and clinicians a powerful means by which to develop strategies to treat patients with inherited retinal dystrophies. In this review we will discuss the current developments in CRISPR-Cas9 gene editing in vivo in animal models and in vitro in patient-derived cells to study and treat inherited retinal degenerative diseases.
基因矫正策略是治疗遗传性视网膜退行性疾病的一种有效方法，这些疾病是全球范围内不可逆转失明的主要原因。单基因缺陷导致了大多数视网膜营养不良。如果在疾病早期进行基因增强，将会有很大的希望，但许多患者携带的基因突变太大，无法包装到腺相关病毒载体中，有些基因在异源启动子过表达时会引起视网膜毒性。除了上述挑战外，一些患者在诊断时已经发生了显著的光感受器细胞丧失，使得基因替代疗法不足以治疗疾病。这些患者将需要细胞替代来恢复有用的视力。幸运的是，诱导多能干细胞和 CRISPR-Cas9 基因编辑技术的出现为研究人员和临床医生提供了一种强大的手段，用于开发治疗遗传性视网膜退行性疾病患者的策略。在这篇综述中，我们将讨论在动物模型中进行的 CRISPR-Cas9 基因编辑的最新进展，以及在患者来源细胞中进行的体外研究，以研究和治疗遗传性视网膜退行性疾病。
