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Reading frame correction by targeted genome editing restores dystrophin expression in cells from duchenne muscular dystrophy patients

Publication ,  Journal Article
Ousterout, DG; Perez-Pinera, P; Thakore, PI; Kabadi, AM; Brown, MT; Qin, X; Fedrigo, O; Mouly, V; Tremblay, JP; Gersbach, CA
Published in: Molecular Therapy
2013

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. © The American Society of Gene and Cell Therapy.

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Published In

Molecular Therapy

DOI

ISSN

1525-0016

Publication Date

2013

Volume

21

Issue

9

Start / End Page

1718 / 1726

Related Subject Headings

  • Biotechnology
  • 11 Medical and Health Sciences
  • 10 Technology
  • 06 Biological Sciences
 

Citation

APA
Chicago
ICMJE
MLA
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Ousterout, D. G., Perez-Pinera, P., Thakore, P. I., Kabadi, A. M., Brown, M. T., Qin, X., … Gersbach, C. A. (2013). Reading frame correction by targeted genome editing restores dystrophin expression in cells from duchenne muscular dystrophy patients. Molecular Therapy, 21(9), 1718–1726. https://doi.org/10.1038/mt.2013.111
Ousterout, D. G., P. Perez-Pinera, P. I. Thakore, A. M. Kabadi, M. T. Brown, X. Qin, O. Fedrigo, V. Mouly, J. P. Tremblay, and C. A. Gersbach. “Reading frame correction by targeted genome editing restores dystrophin expression in cells from duchenne muscular dystrophy patients.” Molecular Therapy 21, no. 9 (2013): 1718–26. https://doi.org/10.1038/mt.2013.111.
Ousterout DG, Perez-Pinera P, Thakore PI, Kabadi AM, Brown MT, Qin X, et al. Reading frame correction by targeted genome editing restores dystrophin expression in cells from duchenne muscular dystrophy patients. Molecular Therapy. 2013;21(9):1718–26.
Ousterout, D. G., et al. “Reading frame correction by targeted genome editing restores dystrophin expression in cells from duchenne muscular dystrophy patients.” Molecular Therapy, vol. 21, no. 9, 2013, pp. 1718–26. Scival, doi:10.1038/mt.2013.111.
Ousterout DG, Perez-Pinera P, Thakore PI, Kabadi AM, Brown MT, Qin X, Fedrigo O, Mouly V, Tremblay JP, Gersbach CA. Reading frame correction by targeted genome editing restores dystrophin expression in cells from duchenne muscular dystrophy patients. Molecular Therapy. 2013;21(9):1718–1726.
Journal cover image

Published In

Molecular Therapy

DOI

ISSN

1525-0016

Publication Date

2013

Volume

21

Issue

9

Start / End Page

1718 / 1726

Related Subject Headings

  • Biotechnology
  • 11 Medical and Health Sciences
  • 10 Technology
  • 06 Biological Sciences