Cas9-mediated allelic exchange repairs compound heterozygous recessive mutations in mice

• Published in: Nature biotechnology Vol. 36; no. 9; pp. 839 - 842
• Main Authors: Wang, Dan, Li, Jia, Song, Chun-Qing, Tran, Karen, Mou, Haiwei, Wu, Pei-Hsuan, Tai, Phillip W L, Mendonca, Craig A, Ren, Lingzhi, Wang, Blake Y, Su, Qin, Gessler, Dominic J, Zamore, Phillip D, Xue, Wen, Gao, Guangping
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2018; Nature Publishing Group
• Subjects: 38/23; 38/77; 38/91; 42/41; 631/61/201; 631/61/201/2110; 64/60; Agriculture; Alleles; Animal models; Animals; Bioinformatics; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; brief-communication; CRISPR-Associated Protein 9; Deoxyribonucleic acid; Dependovirus - genetics; DNA; Exchanging; Gene Editing; Gene mutation; Genes; Genes, Recessive; Genetic disorders; Genetic engineering; Genetic Vectors; Genome editing; Genomes; Genomics; Genotypes; Heterozygote; Life Sciences; Maintenance; Methods; Mice; Mucopolysaccharidoses; Mucopolysaccharidosis; Mutation; Phenotypes; Ribonucleic acid; RNA
• ISSN: 1087-0156; 1546-1696
• DOI: 10.1038/nbt.4219

Diseases caused by different mutations in the two alleles of a gene are treated in mice by Cas-9-induced allelic exchange. We report a genome-editing strategy to correct compound heterozygous mutations, a common genotype in patients with recessive genetic disorders. Adeno-associated viral vector delivery of Cas9 and guide RNA induces allelic exchange and rescues the disease phenotype in mouse models of hereditary tyrosinemia type I and mucopolysaccharidosis type I. This approach recombines non-mutated genetic information present in two heterozygous alleles into one functional allele without using donor DNA templates.