Diseases of the central nervous system (CNS) have historically been among the most difficult to treat using conventional pharmacological approaches. This is due to a confluence of factors, including the limited regenerative capacity and overall complexity of the brain, problems associated with repeated drug administration, and difficulties delivering drugs across the blood-brain barrier (BBB). Viral-mediated gene transfer represents an attractive alternative for the delivery of therapeutic cargo to the nervous system. Crucially, it usually requires only a single injection, whether that be a gene replacement strategy for an inherited disorder or the delivery of a genome- or epigenome-modifying construct for treatment of CNS diseases and disorders. It is thus understandable that considerable effort has been put towards the development of improved vector systems for gene transfer into the CNS. Different viral vectors are of course tailored to their specific applications, but they generally should share several key properties. The ideal viral vector incorporates a high-packaging capacity, efficient gene transfer paired with robust and sustained expression, lack of oncogenicity, toxicity and pathogenicity, and scalable manufacturing for clinical applications. In this review, we will devote attention to viral vectors derived from human immunodeficiency virus type 1 (lentiviral vectors; LVs) and adeno-associated virus (AAVs). The high interest in these viral delivery systems vectors is due to: (i) robust delivery and long-lasting expression; (ii) efficient transduction into postmitotic cells, including the brain; (iii) low immunogenicity and toxicity; and (iv) compatibility with advanced manufacturing techniques. Here, we will outline basic aspects of LV and AAV biology, particularly focusing on approaches and techniques aiming to enhance viral safety. We will also allocate a significant portion of this review to the development and use of LVs and AAVs for delivery into the CNS, with a focus on the genome and epigenome-editing tools based on clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas 9) and the development of novel strategies for the treatment of neurodegenerative diseases (NDDs).

历史上，中枢神经系统疾病一直是使用常规药理学方法最难治疗的疾病。这是由于多种因素的融合，包括有限的再生能力和大脑的整体复杂性，与重复给药相关的问题以及跨血脑屏障（BBB）输送药物的困难。病毒介导的基因转移代表了将治疗性药物递送至神经系统的一种有吸引力的选择。至关重要的是，无论是用于遗传性疾病的基因替代策略，还是用于治疗CNS疾病和疾病的基因组或表观基因组修饰构建物的递送，通常只需要单次注射即可。因此可以理解的是，已经做出了相当大的努力来开发用于将基因转移到CNS中的改进的载体系统。不同的病毒载体当然是针对其特定的应用量身定制的，但是它们通常应该共享几个关键特性。理想的病毒载体具有高包装能力，有效的基因转移，稳健且持续的表达，缺乏致癌性，毒性和致病性以及可扩展的临床应用制造能力。在这篇综述中，我们将专注于源自人类1型免疫缺陷病毒的病毒载体（慢病毒载体； LVs）和腺相关病毒（AAVs）。对这些病毒传递系统载体的高度关注是由于：（i）稳健的传递和持久的表达；（ii）有效转导入有丝分裂后细胞，包括大脑；（iii）低免疫原性和毒性；（iv）与先进制造技术的兼容性。在这里，我们将概述LV和AAV生物学的基本方面，尤其着重于旨在提高病毒安全性的方法和技术。我们还将在本综述中将很大一部分分配给LV和AAV的开发和使用，以将其输送到CNS中，重点关注基于簇状规则间隔的短回文重复序列/ CRISPR相关蛋白的基因组和表观基因组编辑工具9 （CRISPR / Cas 9）和治疗神经退行性疾病（NDD）的新策略的开发。特别关注旨在提高病毒安全性的方法和技术。我们还将在本综述中将很大一部分分配给LV和AAV的开发和使用，以将其输送到CNS中，重点关注基于簇状规则间隔的短回文重复序列/ CRISPR相关蛋白的基因组和表观基因组编辑工具9 （CRISPR / Cas 9）和治疗神经退行性疾病（NDD）的新策略的开发。特别关注旨在提高病毒安全性的方法和技术。我们还将在本综述中将很大一部分分配给LV和AAV的开发和使用，以将其输送到CNS中，重点关注基于簇状规则间隔的短回文重复序列/ CRISPR相关蛋白的基因组和表观基因组编辑工具9 （CRISPR / Cas 9）和治疗神经退行性疾病（NDD）的新策略的开发。