Cytosine and adenine base editing of the brain, liver, retina, heart and skeletal muscle of mice via adeno-associated viruses

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作者
Jonathan M. Levy
Wei-Hsi Yeh
Nachiket Pendse
Jessie R. Davis
Erin Hennessey
Rossano Butcher
Luke W. Koblan
Jason Comander
Qin Liu
David R. Liu
机构
[1] Broad Institute of Harvard and MIT,Merkin Institute of Transformative Technologies in Healthcare
[2] Harvard University,Department of Chemistry and Chemical Biology
[3] Harvard University,Howard Hughes Medical Institute
[4] Harvard Medical School,Program in Speech and Hearing Bioscience and Technology
[5] Massachusetts Eye and Ear Institute,Ocular Genomics Institute
[6] Harvard Medical School,Department of Ophthalmology
来源
Nature Biomedical Engineering | 2020年 / 4卷
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摘要
The success of base editors for the study and treatment of genetic diseases depends on the ability to deliver them in vivo to the relevant cell types. Delivery via adeno-associated viruses (AAVs) is limited by AAV packaging capacity, which precludes the use of full-length base editors. Here, we report the application of dual AAVs for the delivery of split cytosine and adenine base editors that are then reconstituted by trans-splicing inteins. Optimized dual AAVs enable in vivo base editing at therapeutically relevant efficiencies and dosages in the mouse brain (up to 59% of unsorted cortical tissue), liver (38%), retina (38%), heart (20%) and skeletal muscle (9%). We also show that base editing corrects, in mouse brain tissue, a mutation that causes Niemann–Pick disease type C (a neurodegenerative ataxia), slowing down neurodegeneration and increasing lifespan. The optimized delivery vectors should facilitate the efficient introduction of targeted point mutations into multiple tissues of therapeutic interest.
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页码:97 / 110
页数:13
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