Publication Date:
2016-01-02
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760628/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760628/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Long, Chengzu -- Amoasii, Leonela -- Mireault, Alex A -- McAnally, John R -- Li, Hui -- Sanchez-Ortiz, Efrain -- Bhattacharyya, Samadrita -- Shelton, John M -- Bassel-Duby, Rhonda -- Olson, Eric N -- DK-099653/DK/NIDDK NIH HHS/ -- HL-077439/HL/NHLBI NIH HHS/ -- HL-093039/HL/NHLBI NIH HHS/ -- HL-111665/HL/NHLBI NIH HHS/ -- R01 DK099653/DK/NIDDK NIH HHS/ -- R01 HL077439/HL/NHLBI NIH HHS/ -- R01 HL093039/HL/NHLBI NIH HHS/ -- R01 HL111665/HL/NHLBI NIH HHS/ -- U01 HL100401/HL/NHLBI NIH HHS/ -- U01-HL-100401/HL/NHLBI NIH HHS/ -- U54 HD 087351/HD/NICHD NIH HHS/ -- New York, N.Y. -- Science. 2016 Jan 22;351(6271):400-3. doi: 10.1126/science.aad5725. Epub 2015 Dec 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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. ; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. ; 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26721683" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
*CRISPR-Cas Systems
;
Dependovirus
;
Disease Models, Animal
;
Dystrophin/*genetics
;
Exons/genetics
;
Female
;
Forelimb/physiopathology
;
Genetic Therapy/*methods
;
Genome/genetics
;
Hand Strength
;
Male
;
Mice
;
Mice, Inbred mdx
;
Muscle, Skeletal/metabolism
;
Muscular Dystrophy, Duchenne/genetics/*therapy
;
Myocardium/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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