Adenine base editing in an adult mouse model of tyrosinemia

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URI: https://hdl.handle.net/10481/110174
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Autor
Song, Chun-Qing; Jiang, Tingting; Richter, Michelle; Rhym, Luke H.; Koblan, Luke W.; Zafra, María Paz; Schatoff, Emma M.; Doman, Jordan L.; Cao, Yueying; Dow, Lukas E.; Zhu, Lihua Julie; Anderson, Daniel G.; Liu, David R.; Yin, Hao; Xue, Wen
Editorial
Springer Nature
Materia
Base Editing
 
Animal models
 
CRISPR-CAS9
 
Fecha
2020-01
Referencia bibliográfica
Published version: Song, CQ., Jiang, T., Richter, M. et al. Adenine base editing in an adult mouse model of tyrosinaemia. Nat Biomed Eng 4, 125–130 (2020). https://doi.org/10.1038/s41551-019-0357-8
Patrocinador
National Institutes of Health ((NIH) DP2HL137167, P01HL131471 and UG3HL147367); American Cancer Society (129056-RSG-16-093); Lung Cancer Research Foundation, Hyundai Hope on Wheels, UMass CCTS and ALS Association; DARPA HR0011-17-2-0049; US NIH RM1 HG009490, R01 EB022376, U01 AI142756 and R35 GM118062; HHMI, R01 CA195787; K22 CA181280; Marble Center for Cancer Nanomedicine; HHMI National Cancer Institute P30-CA14051; NIH Training Grant T32 GM095450; National Natural Science Foundation of China 31871345; Wuhan University
Resumen
Unlike traditional CRISPR-Cas9 homology-directed repair, base editing can correct point mutations without supplying a DNA-repair template. Here, we show in a mouse model of tyrosinemia that hydrodynamic tail-vein injection of plasmid DNA encoding the adenine base editor (ABE) and a single guide RNA can correct an A>G splice-site mutation. ABE treatment partially restored splicing, generated fumarylacetoacetate hydrolase (Fah)-positive hepatocytes in the liver, and rescued weight loss in the animals. We also generated Fah+ hepatocytes in the liver via lipid-nanoparticle-mediated delivery of chemically modified sgRNA and an mRNA of a codon-optimized base editor that displayed higher base-editing efficiency than the standard ABE. Our findings suggest that adenosine base editing can be used for the correction of genetic disease in adult animals.
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