Erratum: Lentiviral vectors can be used for full-length dystrophin gene therapy.
Erratum: Lentiviral vectors can be used for full-length dystrophin gene therapy.
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DOI：
10.1038/srep46880
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发表时间：
2017-08-29
影响因子：
4.6
通讯作者：
Danos O
中科院分区：
文献类型：
--
作者：
Counsell JR;Asgarian Z;Meng J;Ferrer V;Vink CA;Howe SJ;Waddington SN;Thrasher AJ;Muntoni F;Morgan JE;Danos O
杜氏肌营养不良症（DMD）是由患者肌纤维中肌营养不良蛋白表达的缺乏引起的。目前的DMD基因治疗策略依赖于肌营养不良蛋白的内部缺失形式的表达，缺失重要的功能结构域。全长肌养蛋白的病毒基因转移可以恢复野生型功能，尽管这种方法受到重组病毒载体的有限能力的限制。慢病毒载体可以包装比腺相关病毒更大的转基因，但慢病毒载体仍然在很大程度上未开发的全长肌营养不良蛋白交付。在我们的工作中，我们已经证明慢病毒载体可以包装和递送与肌营养不良蛋白大小相似的插入片段。我们报告了一种在慢病毒中递送大转基因的新方法，在该方法中，我们证明了在逆转录过程中利用重组事件的“模板转换”慢病毒载体的概念验证。在这项工作中，我们发现一个标准的，未经修饰的慢病毒载体是有效的提供全长肌营养不良蛋白的靶细胞，在超过15,000个碱基对的总基因组负载。我们已经证明了这种载体的基因治疗恢复肌营养不良蛋白在DMD成肌细胞，肌营养不良蛋白表达肌细胞分化后肌管的肌膜。最终，我们的工作证明了慢病毒可用于永久性全长肌营养不良蛋白基因治疗的概念验证，这在开发DMD的有效治疗方法方面取得了重大进展。
Duchenne Muscular Dystrophy (DMD) is caused by a lack of dystrophin expression in patient muscle fibres. Current DMD gene therapy strategies rely on the expression of internally deleted forms of dystrophin, missing important functional domains. Viral gene transfer of full-length dystrophin could restore wild-type functionality, although this approach is restricted by the limited capacity of recombinant viral vectors. Lentiviral vectors can package larger transgenes than adeno-associated viruses, yet lentiviral vectors remain largely unexplored for full-length dystrophin delivery. In our work, we have demonstrated that lentiviral vectors can package and deliver inserts of a similar size to dystrophin. We report a novel approach for delivering large transgenes in lentiviruses, in which we demonstrate proof-of-concept for a ‘template-switching’ lentiviral vector that harnesses recombination events during reverse-transcription. During this work, we discovered that a standard, unmodified lentiviral vector was efficient in delivering full-length dystrophin to target cells, within a total genomic load of more than 15,000 base pairs. We have demonstrated gene therapy with this vector by restoring dystrophin expression in DMD myoblasts, where dystrophin was expressed at the sarcolemma of myotubes after myogenic differentiation. Ultimately, our work demonstrates proof-of-concept that lentiviruses can be used for permanent full-length dystrophin gene therapy, which presents a significant advancement in developing an effective treatment for DMD.
影响因子：
4.6
作者：
Counsell JR;Asgarian Z;Meng J;Ferrer V;Vink CA;Howe SJ;Waddington SN;Thrasher AJ;Muntoni F;Morgan JE;Danos O
通讯作者：
Danos O