For more than 10 years, gene therapy for neurological diseases has experienced intensive research growth and more recently therapeutic interventions for multiple indications. Beneficial results in several phase 1/2 clinical studies, together with improved vector technology have advanced gene therapy for the central nervous system (CNS) in a new era of development. Although most initial strategies have focused on orphan genetic diseases, such as lysosomal storage diseases, more complex and widespread conditions like Alzheimer's disease, Parkinson's disease, epilepsy, or chronic pain are increasingly targeted for gene therapy. Increasing numbers of applications and patients to be treated will require improvement and simplification of gene therapy protocols to make them accessible to the largest number of affected people. Although vectors and manufacturing are a major field of academic research and industrial development, there is a growing need to improve, standardize, and simplify delivery methods. Delivery is the major issue for CNS therapies in general, and particularly for gene therapy. The blood–brain barrier restricts the passage of vectors; strategies to bypass this obstacle are a central focus of research. In this study, we present the different ways that can be used to deliver gene therapy products to the CNS. We focus on results obtained in large animals that have allowed the transfer of protocols to human patients and have resulted in the generation of clinical data. We discuss the different routes of administration, their advantages, and their limitations. We describe techniques, equipment, and protocols and how they should be selected for safe delivery and improved efficiency for the next generation of gene therapy trials for CNS diseases.

中文翻译：

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神经系统疾病基因治疗的挑战：实现中枢神经系统有效递送的策略和工具

十多年来，神经系统疾病的基因治疗经历了密集的研究增长以及最近针对多种适应症的治疗干预。几项 1/2 期临床研究的有益结果以及改进的载体技术使中枢神经系统 (CNS) 的基因治疗进入了一个新的发展时代。尽管大多数最初的策略都集中在孤儿遗传疾病，如溶酶体贮积病，但更复杂和广泛的疾病，如阿尔茨海默病、帕金森病、癫痫或慢性疼痛，越来越多地成为基因治疗的目标。越来越多的应用程序和要治疗的患者将需要改进和简化基因治疗方案，以使最多的受影响人群能够使用它们。尽管载体和制造是学术研究和工业发展的主要领域，但改进、标准化和简化交付方法的需求日益增长。一般而言，递送是 CNS 治疗的主要问题，尤其是基因治疗。血脑屏障限制了载体的通过；绕过这一障碍的策略是研究的中心焦点。在这项研究中，我们介绍了可用于将基因治疗产品输送到中枢神经系统的不同方法。我们专注于在大型动物中获得的结果，这些结果允许将方案转移给人类患者并导致产生临床数据。我们讨论了不同的给药途径、它们的优点和局限性。我们描述技术、设备、