ImportanceGene editing using clustered regularly interspaced short palindromic repeats (CRISPR) holds the promise to arrest or cure monogenic disease if it can be determined which genetic change to create without inducing unintended cellular dysfunction and how to deliver this technology to the target organ reliably and safely. Clinical trials for blood and liver disorders, for which delivery of CRISPR is not limiting, show promise, yet no trials have begun for central nervous system (CNS) indications.ObservationsThe CNS is arguably the most challenging target given its innate exclusion of large molecules and its defenses against bacterial invasion (from which CRISPR originates). Herein, the types of CRISPR editing (DNA cutting, base editing, and templated repair) and how these are applied to different genetic variants are summarized. The challenges of delivering genome editors to the CNS, including the viral and nonviral delivery vehicles that may ultimately circumvent these challenges, are discussed. Also, ways to minimize the potential in vivo genotoxic effects of genome editors through delivery vehicle design and preclinical off-target testing are considered. The ethical considerations of germline editing, a potential off-target outcome of any gene editing therapy, are explored. The unique regulatory challenges of a human-specific therapy that cannot be derisked solely in animal models are also discussed.Conclusions and RelevanceAn understanding of both the potential benefits and challenges of CRISPR gene therapy better informs the scientific, clinical, regulatory, and timeline considerations of developing CRISPR gene therapy for neurologic diseases.

中文翻译：

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构建中枢神经系统 CRISPR 基因疗法

重要性如果能够确定在不引起意外细胞功能障碍的情况下产生哪些基因变化，以及如何将该技术可靠、安全地传递到靶器官，那么使用成簇规则间隔短回文重复序列 (CRISPR) 进行基因编辑有望阻止或治愈单基因疾病。针对血液和肝脏疾病的临床试验（CRISPR 的递送不受限制）显示出希望，但尚未开始针对中枢神经系统 (CNS) 适应症的试验。 观察结果 CNS 可以说是最具挑战性的目标，因为它天生排除大分子和它对细菌入侵的防御（CRISPR 源自于此）。本文总结了 CRISPR 编辑的类型（DNA 切割、碱基编辑和模板化修复）以及它们如何应用于不同的遗传变异。讨论了将基因组编辑器传递到中枢神经系统的挑战，包括最终可能规避这些挑战的病毒和非病毒传递载体。此外，还考虑了通过运载工具设计和临床前脱靶测试来最小化基因组编辑器潜在的体内基因毒性效应的方法。探讨了种系编辑的伦理考虑，这是任何基因编辑疗法的潜在脱靶结果。还讨论了仅在动物模型中无法避免的人类特异性疗法的独特监管挑战。结论和相关性了解 CRISPR 基因疗法的潜在益处和挑战可以更好地为科学、临床、监管和时间表考虑提供信息。开发针对神经系统疾病的 CRISPR 基因疗法。