Adenine base editing in an adult mouse model of tyrosinemia 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 Base Editing Animal models CRISPR-CAS9 W.X. was supported by grants from the National Institutes of Health ((NIH) DP2HL137167, P01HL131471 and UG3HL147367), American Cancer Society (129056-RSG-16-093), the Lung Cancer Research Foundation, Hyundai Hope on Wheels, UMass CCTS and ALS Association. This work was supported by DARPA HR0011-17-2-0049; US NIH RM1 HG009490, R01 EB022376, U01 AI142756 and R35 GM118062; and HHMI (to D.R.L.), and R01 CA195787; K22 CA181280 (to L.E.D.). This work was supported in part by the Marble Center for Cancer Nanomedicine and a Cancer Center Support (core) grant P30-CA14051 from the National Cancer Institute. M.R. was supported by the HHMI Hanna H. Gray Fellowship. L.W.K. is an NSF Graduate Research Fellow and was supported NIH Training Grant T32 GM095450. H.Y. was supported by the National Natural Science Foundation of China 31871345, the Young Thousand Talented Program from Wuhan University and startup funding from Wuhan University. Supplementary Material Refer to Web version on PubMed Central for supplementary material. 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. 2026-01-23T12:53:53Z 2026-01-23T12:53:53Z 2020-01 journal article 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 https://hdl.handle.net/10481/110174 10.1038/s41551-019-0357-8 eng open access Springer Nature