Inherited retinal degenerations (IRDs) are a leading cause of blindness. Although gene-supplementation therapies have been developed, they are only available for a small proportion of recessive IRD mutations. In contrast, genome editing using clustered-regularly interspaced short palindromic repeats (CRISPR) CRISPR-associated (Cas) systems could provide alternative therapeutic avenues for treating a wide range of genetic retinal diseases through targeted knockdown or correction of mutant alleles. Progress in this rapidly evolving field has been highlighted by recent Food and Drug Administration clinical trial approval for EDIT-101 (Editas Medicine, Inc., Cambridge, MA), which has demonstrated efficacious genome editing in a mouse model of CEP290-associated Leber congenital amaurosis and safety in nonhuman primates. Nonetheless, there remains a significant number of challenges to developing clinically viable retinal genome-editing therapies. In particular, IRD-causing mutations occur in more than 200 known genes, with considerable heterogeneity in mutation type and position within each gene. Additionally, there are remaining safety concerns over long-term expression of Cas9 in vivo. This review highlights (i) the technological advances in gene-editing technology, (ii) major safety concerns associated with retinal genome editing, and (iii) potential strategies for overcoming these challenges to develop clinical therapies.

中文翻译：

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治疗人类视网膜变性的基因组编辑策略

遗传性视网膜变性 (IRD) 是失明的主要原因。尽管已经开发出基因补充疗法，但它们仅适用于一小部分隐性 IRD 突变。相比之下，使用成簇规律间隔的短回文重复 (CRISPR) CRISPR 相关 (Cas) 系统的基因组编辑可以提供替代治疗途径，通过靶向敲低或校正突变等位基因来治疗多种遗传性视网膜疾病。最近食品和药物管理局批准的 EDIT-101 临床试验（Editas Medicine, Inc., Cambridge, MA）突显了这一快速发展领域的进展，该试验在 CEP290 小鼠模型中证明了有效的基因组编辑-相关的 Leber 先天性黑蒙症和非人灵长类动物的安全性。尽管如此，开发临床上可行的视网膜基因组编辑疗法仍然存在大量挑战。特别是，IRD 引起的突变发生在 200 多个已知基因中，每个基因的突变类型和位置具有相当大的异质性。此外，在体内长期表达 Cas9 仍存在安全问题。这篇综述强调了 (i) 基因编辑技术的技术进步，(ii) 与视网膜基因组编辑相关的主要安全问题，以及 (iii) 克服这些挑战以开发临床疗法的潜在策略。