TY - JOUR
T1 - Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy
AU - Amoasii, Leonela
AU - Hildyard, John C.W.
AU - Li, Hui
AU - Sanchez-Ortiz, Efrain
AU - Mireault, Alex
AU - Caballero, Daniel
AU - Harron, Rachel
AU - Stathopoulou, Thaleia Rengina
AU - Massey, Claire
AU - Shelton, John M.
AU - Bassel-Duby, Rhonda
AU - Piercy, Richard J.
AU - Olson, Eric N.
N1 - Publisher Copyright:
© 2018 The Authors.
PY - 2018/10/5
Y1 - 2018/10/5
N2 - Mutations in the gene encoding dystrophin, a protein that maintains muscle integrity and function, cause Duchenne muscular dystrophy (DMD). The deltaE50-MD dog model of DMD harbors a mutation corresponding to a mutational "hotspot" in the human DMD gene. We used adeno-associated viruses to deliver CRISPR gene editing components to four dogs and examined dystrophin protein expression 6 weeks after intramuscular delivery (n = 2) or 8 weeks after systemic delivery (n = 2). After systemic delivery in skeletal muscle, dystrophin was restored to levels ranging from 3 to 90% of normal, depending on muscle type. In cardiac muscle, dystrophin levels in the dog receiving the highest dose reached 92% of normal. The treated dogs also showed improved muscle histology. These large-animal data support the concept that, with further development, gene editing approaches may prove clinically useful for the treatment of DMD.
AB - Mutations in the gene encoding dystrophin, a protein that maintains muscle integrity and function, cause Duchenne muscular dystrophy (DMD). The deltaE50-MD dog model of DMD harbors a mutation corresponding to a mutational "hotspot" in the human DMD gene. We used adeno-associated viruses to deliver CRISPR gene editing components to four dogs and examined dystrophin protein expression 6 weeks after intramuscular delivery (n = 2) or 8 weeks after systemic delivery (n = 2). After systemic delivery in skeletal muscle, dystrophin was restored to levels ranging from 3 to 90% of normal, depending on muscle type. In cardiac muscle, dystrophin levels in the dog receiving the highest dose reached 92% of normal. The treated dogs also showed improved muscle histology. These large-animal data support the concept that, with further development, gene editing approaches may prove clinically useful for the treatment of DMD.
UR - http://www.scopus.com/inward/record.url?scp=85053601183&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85053601183&partnerID=8YFLogxK
U2 - 10.1126/science.aau1549
DO - 10.1126/science.aau1549
M3 - Article
C2 - 30166439
AN - SCOPUS:85053601183
SN - 0036-8075
VL - 362
SP - 86
EP - 91
JO - Science
JF - Science
IS - 6410
ER -