Destination Brain: the Past, Present, and Future of Therapeutic Gene Delivery.
Destination Brain: the Past, Present, and Future of Therapeutic Gene Delivery.
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DOI：
10.1007/s11481-016-9724-3
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发表时间：
2017-03
期刊：
影响因子：
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通讯作者：
Ghorpade A
中科院分区：
文献类型：
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作者：
Joshi CR;Labhasetwar V;Ghorpade A
神经性疾病和障碍(NDDS)是一个重大的社会负担，目前基于药物和生物的治疗策略已被证明不足以减轻这种负担。与传统系统相比，基因疗法是治疗NDDS的合适选择，因为它可以量身定做，专门改变选定的基因表达，逆转疾病表型，恢复正常功能。多年来，随着RNA干扰和基因组编辑技术的出现，基因治疗的范围已经扩大。因此，针对中枢神经系统(CNS)的基因传递研究取得了令人鼓舞的结果，导致它们从临床前试验过渡到临床试验。随着我们转向一个令人兴奋的基因治疗时代，回顾现有的关于中枢神经系统相关基因传递的文献是必要的。在这方面，这一审查是及时的，因为它分析了过去20年的关键挑战和主要发现，并评估了脑基因交付的未来前景。我们强调的主要领域包括基因治疗中的生理和药理学挑战，基于功能的理想细胞靶点的选择，可用的治疗方式，以及作为载体系统的病毒载体和纳米颗粒的多样性。此外，我们提出了一些关键问题的合理答案，如规避低血脑屏障通透性的策略，最适合靶向的中枢神经系统细胞类型。我们比较和对比了过去和目前临床试验中使用的递送系统中测试的病毒载体的优缺点。基因载体的设计挑战也在细胞特异性启动子的背景下进行了评估。在BASE到床边基因治疗翻译的背景下，讨论了最近的基因治疗临床试验的主要挑战和报告的结果，评估病毒载体和纳米粒子。我们通过结合基因传递挑战、可用的载体系统和对神经发病机制的全面分析来总结这篇综述，以概述中枢神经系统靶向基因治疗的未来前景。
Neurological diseases and disorders (NDDs) present a significant societal burden and currently available drug- and biological-based therapeutic strategies have proven inadequate to alleviate it. Gene therapy is a suitable alternative to treat NDDs compared to conventional systems since it can be tailored to specifically alter select gene expression, reverse disease phenotype and restore normal function. The scope of gene therapy has broadened over the years with the advent of RNA interference and genome editing technologies. Consequently, encouraging results from central nervous system (CNS)-targeted gene delivery studies have led to their transition from preclinical to clinical trials. As we shift to an exciting gene therapy era, a retrospective of available literature on CNS-associated gene delivery is in order. This review is timely in this regard, since it analyzes key challenges and major findings from the last two decades and evaluates future prospects of brain gene delivery. We emphasize major areas consisting of physiological and pharmacological challenges in gene therapy, function-based selection of an ideal cellular target, available therapy modalities, and diversity of viral vectors and nanoparticles as vehicle systems. Further, we present plausible answers to key questions such as strategies to circumvent low blood-brain barrier permeability, most suitable CNS cell types for targeting. We compare and contrast pros and cons of the tested viral vectors in context of delivery systems used in past and current clinical trials. Gene vector design challenges are also evaluated in the context of cell-specific promoters. Key challenges and findings reported for recent gene therapy clinical trials, assessing viral vectors and nanoparticles, are discussed in the context of bench to bedside gene therapy translation. We conclude this review by tying together gene delivery challenges, available vehicle systems and comprehensive analysis of neuropathogenesis to outline future prospects of CNS-targeted gene therapies.