Piguet Françoise, de Saint Denis Timothée, Audouard Emilie, Beccaria Kevin, André Arthur, Wurtz Guillaume, Schatz Raphael, Alves Sandro, Sevin Caroline, Zerah Michel, Cartier Nathalie
NeuroGenCell, INSERM U1127, Paris Brain Institute (ICM), Sorbonne University, CNRS, AP-HP, University Hospital Pitié-Salpêtrière, Paris, France.
APHP, Department of Pediatric Neurosurgery, Hôpital Necker-Enfants Malades, APHP Centre. Université de Paris, Paris, France.
Hum Gene Ther. 2021 Apr;32(7-8):349-374. doi: 10.1089/hum.2020.105. Epub 2021 Jan 26.
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.
十多年来，用于神经疾病的基因治疗经历了深入的研究发展，最近还开展了针对多种适应症的治疗干预。多项1/2期临床研究取得的有益成果，以及改进的载体技术，使中枢神经系统（CNS）基因治疗进入了一个新的发展阶段。尽管最初的大多数策略都集中在罕见遗传病上，如溶酶体贮积症，但诸如阿尔茨海默病、帕金森病、癫痫或慢性疼痛等更复杂、更普遍的病症也越来越多地成为基因治疗的目标。越来越多的应用和待治疗患者将需要改进和简化基因治疗方案，以使更多受影响的人能够接受治疗。尽管载体和生产是学术研究和产业发展的一个主要领域，但改进、标准化和简化递送方法的需求也日益增长。递送是一般中枢神经系统治疗的主要问题，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核心重点。在本研究中，我们介绍了可用于将基因治疗产品递送至中枢神经系统的不同方法。我们重点关注在大型动物身上取得的成果，这些成果使得方案能够转化应用于人类患者，并产生了临床数据。我们讨论了不同的给药途径、它们的优点和局限性。我们描述了技术、设备和方案，以及在针对中枢神经系统疾病的下一代基因治疗试验中应如何选择它们以实现安全递送和提高效率。
