Effective and Accurate Gene Silencing by a Recombinant AAV-Compatible MicroRNA Scaffold.,Molecular Therapy

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Effective and Accurate Gene Silencing by a Recombinant AAV-Compatible MicroRNA Scaffold.
Molecular Therapy ( IF 12.4 ) Pub Date : 2019-11-27 , DOI: 10.1016/j.ymthe.2019.11.018
Jun Xie ₁ , Phillip W L Tai ₂ , Alexander Brown ₂ , Shoufang Gong ₂ , Sha Zhu ₂ , Yi Wang ₃ , Chengjian Li ₄ , Cansu Colpan ₅ , Qin Su ₆ , Ran He ₆ , Hong Ma ₆ , Jia Li ₂ , Hanqing Ye ₂ , Jihye Ko ₆ , Phillip D Zamore ₅ , Guangping Gao ₁

Affiliation

Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA; Viral Vector Core, University of Massachusetts Medical School, Worcester, MA, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA.
Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA, USA; Research Unit of Infection and Immunity, Department of Pathophysiology, West China College of Basic and Forensic Medicine, Sichuan University, Chengdu, Sichuan, People's Republic of China.
Fornax Biotech, Worcester, MA, USA.
RNA Therapeutics Institute and Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, MA, USA.
Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA; Viral Vector Core, University of Massachusetts Medical School, Worcester, MA, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA, USA.

Short hairpin RNAs that are delivered by recombinant adeno-associated virus (rAAV) have the potential to elicit long-term RNAi therapy for human disease. However, the discovery that short hairpin sequences can cause truncation of the rAAV genome calls into question the efficiency and gene-silencing specificity of this strategy in humans. Here, we report that embedding the guide strand of a small silencing RNA into an artificial microRNA (miRNA) scaffold derived from mouse miRNA-33 ensures rAAV genomic integrity and reduces off-targeting by 10-fold, while maintaining effective in vivo target gene repression in mice.

中文翻译：

通过重组AAV兼容的MicroRNA支架进行有效而准确的基因沉默。

由重组腺相关病毒（rAAV）传递的短发夹RNA具有引发人类疾病长期RNAi治疗的潜力。但是，短发夹序列会导致rAAV基因组被截断的发现使人们对该策略在人类中的效率和基因沉默特异性产生了疑问。在这里，我们报告说，将小沉默RNA的引导链嵌入源自小鼠miRNA-33的人工microRNA（miRNA）支架中，可确保rAAV基因组完整性并降低脱靶10倍，同时保持有效的体内靶基因抑制在小鼠中。

更新日期：2019-11-28

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