Department of Neurology, Stem Cell Program and Gene Therapy Center, UC Davis Medical Center, Sacramento, CA, United States.
Curr Neuropharmacol. 2021;19(12):2125-2140. doi: 10.2174/1570159X19666210517144044.
Advancements in programmable DNA-Binding Proteins (DBDs) that target the genome, such as zinc fingers, transcription activator-like effectors, and Cas9, have broadened drug target design beyond traditional protein substrates. Effective delivery methodologies remain a major barrier in targeting the central nervous system. Currently, adeno-associated virus is the most wellvalidated delivery system for the delivery of DBDs towards the central nervous with multiple, ongoing clinical trials. While effective in transducing neuronal cells, viral delivery systems for DBDs remain problematic due to inherent viral packaging limits or immune responses that hinder translational potential. Direct administration of DBDs or encapsulation in lipid nanoparticles may provide alternative means towards delivering gene therapies into the central nervous system. This review will evaluate the strengths and limitations of current DBD delivery strategies in vivo. Furthermore, this review will discuss the use of adult stem cells as a putative delivery vehicle for DBDs and the potential advantages that these systems have over previous methodologies.
可编程 DNA 结合蛋白（DBDs）在基因组靶向方面的进展，如锌指蛋白、转录激活子样效应物和 Cas9，已经将药物靶点设计扩展到了传统的蛋白质底物之外。有效的递药方法仍然是靶向中枢神经系统的主要障碍。目前，腺相关病毒是将 DBD 递送到中枢神经系统最有效的递药系统，有多个正在进行的临床试验。虽然在转导神经元细胞方面非常有效，但由于病毒包装限制或阻碍转化潜力的免疫反应，病毒递药系统对于 DBD 仍然存在问题。DBD 的直接给药或封装在脂质纳米粒中可能为将基因疗法递送到中枢神经系统提供替代方法。本文将评估体内现有 DBD 递药策略的优缺点。此外，本文还将讨论将成体干细胞用作 DBD 递药载体的可能性，以及这些系统相对于以前的方法具有的潜在优势。
