Cytosine and adenine base editing of the brain, liver, retina, heart and skeletal muscle of mice via adeno-associated viruses
Authors: Jessie R Davis
David R Liu
Erin Hennessey
Rossano Butcher
Wei-Hsi Yeh
Jason Comander
Nachiket Pendse
Jonathan M Levy
Qin Liu
Luke W Koblan
Journal: Nature biomedical engineering (2020)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: base editors; adeno-associated viruses; AAVs; split cytosine; adenine
Affiliations: Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA, USA., Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA., Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA., Program in Speech and Hearing Bioscience and Technology, Harvard Medical School, Boston, MA, USA., Ocular Genomics Institute, Massachusetts Eye and Ear Institute, Boston, MA, USA., Department of Ophthalmology, Harvard Medical School, Boston, MA, USA., Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA, USA. ., Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA. ., Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA. .

Abstract:  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. 

Retracted: No

PubPeer comments:
 Figure 3 appears to have image duplications ![file] , 
 Due to my busy work, I didn t see your email until today. Thank you very much for pointing out these mistakes. I am the corresponding author of the article, and these data were collected and provided by the first author. We will inform him to check the figures carefully and respons you as soon as possible. Sincerely, Qionghua Chen , 
 Deer Peer uff01Thank you for pointing this out for us. Recently, we carefully checked the original data. Meanwhile, we also communicated with the first author. After that, we can confirm that three repeated experiments were carried out strictly. The reason for such low-level mistake may be that too many photos were taken and saved in each group, then mistakes maybe occur in the selection of photos for generating figure 3 in the final stage, resulting figure 3 appear to have image duplications. We have contacted with the editors for correction. This incident shows that we are not rigorous enough, and we will learn from it in the future. Thank you again for your valuable advice! Your sincerely, Qionghua Chen ,