Adenine base editing in mouse embryos and an adult mouse model of Duchenne muscular dystrophy
| Autor: | Da Eun Kim, Sangtae Kim, Seuk Min Ryu, Jin-Soo Kim, Hyun Ji Lee, Heon Seok Kim, Eugene Chung, Kyoungmi Kim, Gayoung Baek, Kayeong Lim, Taeyoung Koo |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Albinism Duchenne muscular dystrophy Mutant Nonsense mutation Adenine deaminase Biomedical Engineering Bioengineering Biology Applied Microbiology and Biotechnology Dystrophin 03 medical and health sciences Mice 0302 clinical medicine medicine Animals Humans Guide RNA Muscular dystrophy Gene Gene Editing Mice Knockout Base Sequence Monophenol Monooxygenase Point mutation Adenine DNA Genetic Therapy medicine.disease Mice Mutant Strains Cell biology Muscular Dystrophy Duchenne Disease Models Animal 030104 developmental biology HEK293 Cells Molecular Medicine 030217 neurology & neurosurgery Biotechnology Targeted Gene Repair |
| Zdroj: | Nature biotechnology. 36(6) |
| ISSN: | 1546-1696 |
| Popis: | Adenine base editors (ABEs) composed of an engineered adenine deaminase and the Streptococcus pyogenes Cas9 nickase enable adenine-to-guanine (A-to-G) single-nucleotide substitutions in a guide RNA (gRNA)-dependent manner. Here we demonstrate application of this technology in mouse embryos and adult mice. We also show that long gRNAs enable adenine editing at positions one or two bases upstream of the window that is accessible with standard single guide RNAs (sgRNAs). We introduced the Himalayan point mutation in the Tyr gene by microinjecting ABE mRNA and an extended gRNA into mouse embryos, obtaining Tyr mutant mice with an albino phenotype. Furthermore, we delivered the split ABE gene, using trans-splicing adeno-associated viral vectors, to muscle cells in a mouse model of Duchenne muscular dystrophy to correct a nonsense mutation in the Dmd gene, demonstrating the therapeutic potential of base editing in adult animals. |
| Databáze: | OpenAIRE |
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