Adenine base editing in an adult mouse model of tyrosinaemia.
Chun-Qing SongTingting JiangMichelle RichterLuke H RhymLuke W KoblanMaria Paz ZafraEmma M SchatoffJordan L DomanYueying CaoLukas E DowJulie Lihua ZhuDaniel G AndersonDavid R LiuHao YinWen XuePublished in: Nature biomedical engineering (2019)
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.
Keyphrases
- crispr cas
- genome editing
- mouse model
- dna repair
- weight loss
- dna damage
- magnetic resonance
- bariatric surgery
- type diabetes
- gene expression
- genome wide
- adipose tissue
- computed tomography
- skeletal muscle
- mass spectrometry
- body mass index
- metabolic syndrome
- liver injury
- drug induced
- magnetic resonance imaging
- single molecule
- nucleic acid
- young adults
- obese patients
- copy number
- circulating tumor cells
- glycemic control