Pre-clinical Safety and Off-Target Studies to Support Translation of AAV-Mediated RNAi Therapy for FSHD.
Pre-clinical Safety and Off-Target Studies to Support Translation of AAV-Mediated RNAi Therapy for FSHD.
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临床前安全性和脱靶研究，以支持AAV介导的RNAi治疗FSHD的翻译。
DOI：
10.1016/j.omtm.2017.12.005
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发表时间：
2018-03-16
期刊：
影响因子：
--
通讯作者：
Harper SQ
中科院分区：
文献类型：
--
作者：
Wallace LM;Saad NY;Pyne NK;Fowler AM;Eidahl JO;Domire JS;Griffin DA;Herman AC;Sahenk Z;Rodino-Klapac LR;Harper SQ
近15年前，RNAi作为一种有前景的分子疗法出现。从那时起，两个主要的RNAi平台一直在开发中：寡核苷酸和基因治疗。基于寡核苷酸的方法有了更多的进展，一些有希望的疗法可能很快就会进入市场。相比之下，基于载体的RNAi治疗方法在很大程度上仍停留在临床前领域，迄今临床安全性和有效性数据有限。我们正在开发一种基因治疗方法来治疗常染色体显性遗传性面肩肩周肌营养不良症。我们的策略包括使用腺相关病毒载体传递靶向microRNA表达盒(MiDUX4s)来沉默肌肉毒性基因DUX4。我们以前在小鼠身上证明了这一方法的概念证据，现在我们正在采取额外的步骤来评估与miDUX4过度表达和序列特异性脱靶沉默相关的安全问题。在这项研究中，我们描述了我们的miDUX4序列库在载体设计和扩展方面的改进，并报告了两个miDUX4序列的不同毒性，其中一个有毒，另一个无毒。这项研究提供了重要的数据，有助于推进我们将RNAi基因疗法转化为面肩肱骨肌营养不良症的目标。
RNAi emerged as a prospective molecular therapy nearly 15 years ago. Since then, two major RNAi platforms have been under development: oligonucleotides and gene therapy. Oligonucleotide-based approaches have seen more advancement, with some promising therapies that may soon reach market. In contrast, vector-based approaches for RNAi therapy have remained largely in the pre-clinical realm, with limited clinical safety and efficacy data to date. We are developing a gene therapy approach to treat the autosomal-dominant disorder facioscapulohumeral muscular dystrophy. Our strategy involves silencing the myotoxic gene DUX4 using adeno-associated viral vectors to deliver targeted microRNA expression cassettes (miDUX4s). We previously demonstrated proof of concept for this approach in mice, and we are now taking additional steps here to assess safety issues related to miDUX4 overexpression and sequence-specific off-target silencing. In this study, we describe improvements in vector design and expansion of our miDUX4 sequence repertoire and report differential toxicity elicited by two miDUX4 sequences, of which one was toxic and the other was not. This study provides important data to help advance our goal of translating RNAi gene therapy for facioscapulohumeral muscular dystrophy.
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影响因子：
14.9
作者：
Chen C;Ridzon DA;Broomer AJ;Zhou Z;Lee DH;Nguyen JT;Barbisin M;Xu NL;Mahuvakar VR;Andersen MR;Lao KQ;Livak KJ;Guegler KJ
通讯作者：
Guegler KJ
影响因子：
14.9
作者：
Baker MB;Bao G;Searles CD
通讯作者：
Searles CD
DOI：
10.1038/mt.2016.111
发表时间：
2016-08
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
通讯作者：
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影响因子：
64.8
作者：
Grimm, Dirk;Streetz, Konrad L.;Kay, Mark A.
通讯作者：
Kay, Mark A.
影响因子：
3.5
作者：
Gabriëls, J;Beckers, MC;Belayew, A
通讯作者：
Belayew, A