期刊
MOLECULAR THERAPY
卷 21, 期 9, 页码 1718-1726出版社
CELL PRESS
DOI: 10.1038/mt.2013.111
关键词
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资金
- Hartwell Foundation
- March of Dimes Foundation
- National Institutes of Health [DP2-OD008586]
- Canadian Institute of Health Research
- Association Francaise contre les Myopathies
- Duke Biomedical Engineering Howard Clark Fellowship
- American Heart Association Predoctoral Fellowship
- National Science Foundation
- Pratt Undergraduate Research Fellowship
Genome editing with engineered nucleases has recently emerged as an approach to correct genetic mutations by enhancing homologous recombination with a DNA repair template. However, many genetic diseases, such as Duchenne muscular dystrophy (DMD), can be treated simply by correcting a disrupted reading frame. We show that genome editing with transcription activator-like effector nucleases (TALENs), without a repair template, can efficiently correct the reading frame and restore the expression of a functional dystrophin protein that is mutated in DMD. TALENs were engineered to mediate highly efficient gene editing at exon 51 of the dystrophin gene. This led to restoration of dystrophin protein expression in cells from Duchenne patients, including skeletal myoblasts and dermal fibroblasts that were reprogrammed to the myogenic lineage by MyoD. Finally, exome sequencing of cells with targeted modifications of the dystrophin locus showed no TALEN-mediated off-target changes to the protein-coding regions of the genome, as predicted by in silico target site analysis. This strategy integrates the rapid and robust assembly of active TALENs with an efficient gene-editing method for the correction of genetic diseases caused by mutations in non-essential coding regions that cause frameshifts or premature stop codons.
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