Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects.
Gene therapy for monogenic liver diseases: clinical successes, current challenges and future prospects.
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DOI：
10.1007/s10545-017-0053-3
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发表时间：
2017-07
影响因子：
4.2
通讯作者：
Gissen P
中科院分区：
文献类型：
--
作者：
Baruteau J;Waddington SN;Alexander IE;Gissen P
在过去的十年里，针对血友病B的开创性的肝脏导向基因治疗试验在一次全身注射编码人凝血因子IX基因的腺相关病毒(AAV)衍生载体后，已经取得了持续的临床改善。这些试验证明了AAV技术在治疗单基因肝病方面提供长期临床益处的潜力。事实上，随着十多项针对血友病A和B的正在进行或计划进行的临床试验，以及数十项针对其他遗传性遗传/代谢性肝病的试验计划，临床翻译正在迅速扩大。在相对较短的时间内，基因治疗很可能成为一种常规治疗严重遗传性/代谢性肝病的选择。在本文中，我们旨在总结基因治疗发展的里程碑，介绍不同的载体工具及其在肝脏导向基因治疗中的临床应用。AAV衍生的载体正在成为临床上将基因输送到肝脏的主要候选载体。因此，我们专注于AAV载体的临床应用，以提供已完成和正在进行的基因治疗试验的最新临床结果，并评论该领域在大规模临床翻译方面目前面临的挑战。显然，迫切需要更有效的治疗方法来治疗许多严重的单基因肝病，这将需要对每个适应症进行仔细的风险-收益分析，特别是在儿科。
Over the last decade, pioneering liver-directed gene therapy trials for haemophilia B have achieved sustained clinical improvement after a single systemic injection of adeno-associated virus (AAV) derived vectors encoding the human factor IX cDNA. These trials demonstrate the potential of AAV technology to provide long-lasting clinical benefit in the treatment of monogenic liver disorders. Indeed, with more than ten ongoing or planned clinical trials for haemophilia A and B and dozens of trials planned for other inherited genetic/metabolic liver diseases, clinical translation is expanding rapidly. Gene therapy is likely to become an option for routine care of a subset of severe inherited genetic/metabolic liver diseases in the relatively near term. In this review, we aim to summarise the milestones in the development of gene therapy, present the different vector tools and their clinical applications for liver-directed gene therapy. AAV-derived vectors are emerging as the leading candidates for clinical translation of gene delivery to the liver. Therefore, we focus on clinical applications of AAV vectors in providing the most recent update on clinical outcomes of completed and ongoing gene therapy trials and comment on the current challenges that the field is facing for large-scale clinical translation. There is clearly an urgent need for more efficient therapies in many severe monogenic liver disorders, which will require careful risk-benefit analysis for each indication, especially in paediatrics.
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影响因子：
46.9
作者：
Azuma, Hisaya;Paulk, Nicole;Grompe, Markus
通讯作者：
Grompe, Markus
影响因子：
3.8
作者：
Bell, Peter;Wang, Lili;Wilson, James M.
通讯作者：
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影响因子：
4.2
作者：
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Srivastava, Arun
影响因子：
5.1
作者：
Alba, R;Bosch, A;Chillon, M
通讯作者：
Chillon, M
DOI：
10.1073/pnas.0904514106
发表时间：
2009-09-22
影响因子：
11.1
作者：
Brantly, Mark L.;Chulay, Jeffrey D.;Flotte, Terence R.
通讯作者：
Flotte, Terence R.