title: Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy.
abstract: 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.
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Chengzu
authors.initials: C
authors.lastname: Long
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Leonela
authors.initials: L
authors.lastname: Amoasii
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Alex A
authors.initials: AA
authors.lastname: Mireault
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: McAnally
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Efrain
authors.initials: E
authors.lastname: Sanchez-Ortiz
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Samadrita
authors.initials: S
authors.lastname: Bhattacharyya
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Shelton
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Rhonda
authors.initials: R
authors.lastname: Bassel-Duby
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Sen. Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. eric.olson@utsouthwestern.edu.
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
mesh_terms: D000818:Animals; D064113:CRISPR-Cas Systems; D000229:Dependovirus; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D005552:Forelimb / Q000503:physiopathology; D015316:Genetic Therapy / Q000379:methods*; D016678:Genome / Q000235:genetics; D018737:Hand Strength; D008297:Male; D051379:Mice; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism
chemical_list: D016189:Dystrophin; C085339:apo-dystrophin 1