Coorey Bronte A, Gold Wendy A
School of Medical Sciences, The University of Sydney, Sydney, NSW, Australia.
Molecular Neurobiology Research Laboratory, Kid's Research, Children's Hospital at Westmead, Westmead, NSW, Australia.
Front Genome Ed. 2021 Feb 1;3:623519. doi: 10.3389/fgeed.2021.623519. eCollection 2021.
Monogenic neurological disorders are devastating, affecting hundreds of millions of people globally and present a substantial burden to individuals, carers, and healthcare systems. These disorders are predominantly caused by inherited or variants that result in impairments to nervous system development, neurodegeneration, or impaired neuronal function. No cure exists for these disorders with many being refractory to medication. However, since monogenic neurological disorders have a single causal factor, they are also excellent targets for innovative, therapies such as gene therapy. Despite this promise, gene transfer therapies are limited in that they are only suitable for neurogenetic disorders that fit within the technological reach of these therapies. The limitations include the size of the coding region of the gene, the regulatory control of expression (dosage sensitivity), the mode of expression (e.g., dominant negative) and access to target cells. Gene editing therapies are an alternative strategy to gene transfer therapy as they have the potential of overcoming some of these hurdles, enabling the retention of physiological expression of the gene and offers precision medicine-based therapies where individual variants can be repaired. This review focusses on the existing gene editing technologies for neurogenetic disorders and how these propose to overcome the challenges common to neurogenetic disorders with gene transfer therapies as well as their own challenges.
单基因神经疾病具有毁灭性，全球数亿人受其影响，给患者个人、照料者及医疗系统带来了沉重负担。这些疾病主要由遗传因素或变异引起，导致神经系统发育受损、神经退行性变或神经元功能受损。这些疾病无法治愈，许多对药物治疗无效。然而，由于单基因神经疾病只有一个致病因素，它们也是基因治疗等创新疗法的理想靶点。尽管有这样的前景，但基因转移疗法存在局限性，即仅适用于符合这些疗法技术范围的神经遗传性疾病。这些局限性包括基因编码区的大小、表达的调控控制（剂量敏感性）、表达模式（如显性负性）以及对靶细胞的靶向性。基因编辑疗法是基因转移疗法的一种替代策略，因为它们有可能克服其中一些障碍，实现基因的生理性表达，并提供基于精准医学的疗法，可修复个体变异。本综述聚焦于用于神经遗传性疾病的现有基因编辑技术，以及这些技术如何克服基因转移疗法在神经遗传性疾病中常见的挑战，以及它们自身面临的挑战。
