Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy
By Chengzu Long, L. Amoasii, A. Mireault, John R. McAnally, Hui Li, E. Sánchez-Ortiz, Samadrita Bhattacharyya, J. Shelton, R. Bassel-Duby, E. Olson. Science, 2015
900 citations recorded by the source corpus.
Editing can help build stronger muscles Much of the controversy surrounding the gene-editing technology called CRISPR/Cas9 centers on the ethics of germline editing of human embryos to correct disease-causing mutations. For certain disorders such as muscular dystrophy, it may be possible to achieve therapeutic benefit by editing the faulty gene in somatic cells. In proof-of-concept studies, Long et al., Nelson et al., and Tabebordbar et al. used adeno-associated virus-9 to deliver the CRISPR/Cas9 gene-editing system to young mice with a mutation in the gene coding for dystrophin, a muscle protein deficient in patients with Duchenne muscular dystrophy. Gene editing partially restored dystrophin protein expression in skeletal and cardiac muscle and improved skeletal muscle function. Science, this issue p. 400, p. 403, p. 407 Gene editing via CRISPR-Cas9 restores dystrophin protein and improves muscle function in mouse models of muscular dystrophy. CRISPR/Cas9-mediated genome editing holds clinical potential for treating genetic diseases, such as Duchenne muscular dystrophy (DMD), which is caused by mutations in the dystrophin gene. To correct DMD by skipping mutant dystrophin exons in postnatal muscle tissue in vivo, we used adeno-associated virus–9 (AAV9) to deliver gene-editing components to postnatal mdx mice, a model of DMD. Different modes of AAV9 delivery were systematically tested, including intraperitoneal at postnatal day 1 (P1), intramuscular at P12, and retro-orbital at P18. Each of these methods restored dystrophin protein expression in cardiac and skeletal muscle to varying degrees, and expression increased from 3 to 12 weeks after injection. Postnatal gene editing also enhanced skeletal muscle function, as measured by grip strength tests 4 weeks after injection. This method provides a potential means of correcting mutations responsible for DMD and other monogenic disorders after birth.
Subfields: Molecular Biology
View Paper: https://www.semanticscholar.org/paper/7476b3a9917b7065d50203f86c4b0beb81a785e5
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Citations in the corpus
- Delivering CRISPR: a review of the challenges and approaches (2018, methodology): “This has been accomplished before by Long et al. (2016) who utilized a mini-cytomeglovirus promoter/enhancer with SpCas9 to correct DMD-causing mutations in mice (Figure 6(A)).”
- CRISPR-Cas9-based mutagenesis frequently provokes on-target mRNA misregulation (2019, positive): “These outcomes are currently achieved by using two CRISPR guides that flank a mutated exon 30-32 , or target an exon-specific splice junction using a single guide 33 .”
- Engineering the Delivery System for CRISPR-based Genome Editing (2018, background): “The most common viral vector used for Cas9 delivery is the adeno-associated virus (AAV) vector [14, 28, 29].”