Journal
NATURE BIOMEDICAL ENGINEERING
Volume 4, Issue 1, Pages 125-130Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41551-019-0357-8
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Funding
- NCI NIH HHS [F31 CA224800, T32 CA203702, K22 CA181280, R01 CA195787, P30 CA014051] Funding Source: Medline
- NHGRI NIH HHS [RM1 HG009490] Funding Source: Medline
- NHLBI NIH HHS [DP2 HL137167, UG3 HL147367, P01 HL131471] Funding Source: Medline
- NIAID NIH HHS [U01 AI142756] Funding Source: Medline
- NIBIB NIH HHS [R01 EB022376] Funding Source: Medline
- NIGMS NIH HHS [R35 GM118062, T32 GM095450] Funding Source: Medline
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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. 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.
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