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Adenine base editing in an adult mouse model of tyrosinaemia

2019; Nature Portfolio; Volume: 4; Issue: 1 Linguagem: Inglês

10.1038/s41551-019-0357-8

2157-846X

Chun‐Qing Song, Tingting Jiang, Michelle F. Richter, Luke H. Rhym, Luke W. Koblan, María Paz Zafra, Emma M. Schatoff, Jordan L. Doman, Yueying Cao, Lukas E. Dow, Lihua Julie Zhu, Daniel G. Anderson, David R. Liu, Hao Yin, Wen Xue,

RNA and protein synthesis mechanisms

In contrast to 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 tyrosinaemia that hydrodynamic tail-vein injection of plasmid DNA encoding the adenine base editor (ABE) and a single-guide RNA (sgRNA) 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 mice. We also generated FAH+ hepatocytes in the liver via lipid-nanoparticle-mediated delivery of a chemically modified sgRNA and an mRNA of a codon-optimized base editor that displayed higher base-editing efficiency than the standard ABEs. Our findings suggest that adenine base editing can be used for the correction of genetic diseases in adult animals. Intravenous delivery of an adenine base editor and a single-guide RNA for the Fah gene can correct an A>G splice-site mutation in an adult mouse model of tyrosinaemia.