Fischell Jonathan M, Fishman Paul S
Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, United States.
Front Neurosci. 2021 Sep 24;15:747726. doi: 10.3389/fnins.2021.747726. eCollection 2021.
Despite major advancements in gene therapy technologies, there are no approved gene therapies for diseases which predominantly effect the brain. Adeno-associated virus (AAV) vectors have emerged as the most effective delivery vector for gene therapy owing to their simplicity, wide spread transduction and low immunogenicity. Unfortunately, the blood-brain barrier (BBB) makes IV delivery of AAVs, to the brain highly inefficient. At IV doses capable of widespread expression in the brain, there is a significant risk of severe immune-mediated toxicity. Direct intracerebral injection of vectors is being attempted. However, this method is invasive, and only provides localized delivery for diseases known to afflict the brain globally. More advanced methods for AAV delivery will likely be required for safe and effective gene therapy to the brain. Each step in AAV delivery, including delivery route, BBB transduction, cellular tropism and transgene expression provide opportunities for innovative solutions to optimize delivery efficiency. Intra-arterial delivery with mannitol, focused ultrasound, optimized AAV capsid evolution with machine learning algorithms, synthetic promotors are all examples of advanced strategies which have been developed in pre-clinical models, yet none are being investigated in clinical trials. This manuscript seeks to review these technological advancements, and others, to improve AAV delivery to the brain, and to propose novel strategies to build upon this research. Ultimately, it is hoped that the optimization of AAV delivery will allow for the human translation of many gene therapies for neurodegenerative and other neurologic diseases.
尽管基因治疗技术取得了重大进展，但目前尚无针对主要影响大脑的疾病的获批基因疗法。腺相关病毒（AAV）载体因其简单性、广泛的转导能力和低免疫原性，已成为基因治疗中最有效的递送载体。不幸的是，血脑屏障（BBB）使得通过静脉注射将AAV递送至大脑的效率非常低。在能够在大脑中广泛表达的静脉注射剂量下，存在严重免疫介导毒性的重大风险。目前正在尝试直接向脑内注射载体。然而，这种方法具有侵入性，并且仅为已知在全球范围内影响大脑的疾病提供局部递送。为了实现对大脑的安全有效的基因治疗，可能需要更先进的AAV递送方法。AAV递送的每一步，包括递送途径、血脑屏障转导、细胞嗜性和转基因表达，都为优化递送效率的创新解决方案提供了机会。使用甘露醇进行动脉内递送、聚焦超声、利用机器学习算法优化AAV衣壳进化、合成启动子都是在临床前模型中开发的先进策略的例子，但目前尚无一项在临床试验中进行研究。本手稿旨在回顾这些技术进展以及其他进展，以改善AAV向大脑的递送，并在此研究基础上提出新的策略。最终，希望AAV递送的优化将使许多针对神经退行性疾病和其他神经系统疾病的基因疗法能够转化应用于人类。
