Title

Adenine base editing in an adult mouse model of tyrosinaemia

UMMS Affiliation

RNA Therapeutics Institute; Department of Molecular, Cell and Cancer Biology; Program in Molecular Medicine; Li Weibo Institute for Rare Diseases Research

Publication Date

2020-01-01

Document Type

Article

Disciplines

Bioinformatics | Computational Biology | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Genetic Phenomena | Molecular, Cellular, and Tissue Engineering | Nucleic Acids, Nucleotides, and Nucleosides | Therapeutics

Abstract

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.

Keywords

base editing, genetic diseases, tyrosinaemia

DOI of Published Version

10.1038/s41551-019-0357-8

Source

Song CQ, Jiang T, Richter M, Rhym LH, Koblan LW, Zafra MP, Schatoff EM, Doman JL, Cao Y, Dow LE, Zhu LJ, Anderson DG, Liu DR, Yin H, Xue W. Adenine base editing in an adult mouse model of tyrosinaemia. Nat Biomed Eng. 2020 Jan;4(1):125-130. doi: 10.1038/s41551-019-0357-8. Epub 2019 Feb 25. PMID: 31740768; PMCID: PMC6986236. Link to article on publisher's site

Journal/Book/Conference Title

Nature biomedical engineering

Related Resources

Link to Article in PubMed

PubMed ID

31740768

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