Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy.
Leonela AmoasiiJohn C W HildyardHui LiEfrain Sanchez-OrtizAlex A MireaultDaniel CaballeroRachel C M HarronThaleia-Rengina StathopoulouClaire MasseyJohn M SheltonRhonda Bassel-DubyRichard J PiercyEric N OlsonPublished in: Science (New York, N.Y.) (2018)
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.
Keyphrases
- duchenne muscular dystrophy
- skeletal muscle
- genome wide
- muscular dystrophy
- endothelial cells
- insulin resistance
- poor prognosis
- left ventricular
- binding protein
- heart failure
- dna methylation
- metabolic syndrome
- artificial intelligence
- machine learning
- molecular dynamics
- long non coding rna
- small molecule
- big data
- deep learning
- drug induced
- preterm birth