CRISPR-Cas9 corrects Duchenne muscular dystrophy exon 44 deletion mutations in mice and human cells

Yi Li Min, Hui Li, Cristina Rodriguez-Caycedo, Alex A. Mireault, Jian Huang, John M. Shelton, John R. McAnally, Leonela Amoasii, Pradeep P Mammen, Rhonda S Bassel-Duby, Eric N Olson

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Mutations in the dystrophin gene cause Duchenne muscular dystrophy (DMD), which is characterized by lethal degeneration of cardiac and skeletal muscles. Mutations that delete exon 44 of the dystrophin gene represent one of the most common causes of DMD and can be corrected in ~12% of patients by editing surrounding exons, which restores the dystrophin open reading frame. Here, we present a simple and efficient strategy for correction of exon 44 deletion mutations by CRISPR-Cas9 gene editing in cardiomyocytes obtained from patient-derived induced pluripotent stem cells and in a new mouse model harboring the same deletion mutation. Using AAV9 encoding Cas9 and single guide RNAs, we also demonstrate the importance of the dosages of these gene editing components for optimal gene correction in vivo. Our findings represent a significant step toward possible clinical application of gene editing for correction of DMD.

Original languageEnglish (US)
Article numbereaav4324
JournalScience Advances
Volume5
Issue number3
DOIs
StatePublished - Jan 1 2019

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deletion
mutations
genes
mice
editing
skeletal muscle
degeneration
stem cells
causes
muscles
coding
dosage

ASJC Scopus subject areas

  • Physics and Astronomy (miscellaneous)

Cite this

Min, Y. L., Li, H., Rodriguez-Caycedo, C., Mireault, A. A., Huang, J., Shelton, J. M., ... Olson, E. N. (2019). CRISPR-Cas9 corrects Duchenne muscular dystrophy exon 44 deletion mutations in mice and human cells. Science Advances, 5(3), [eaav4324]. https://doi.org/10.1126/sciadv.aav4324

CRISPR-Cas9 corrects Duchenne muscular dystrophy exon 44 deletion mutations in mice and human cells. / Min, Yi Li; Li, Hui; Rodriguez-Caycedo, Cristina; Mireault, Alex A.; Huang, Jian; Shelton, John M.; McAnally, John R.; Amoasii, Leonela; Mammen, Pradeep P; Bassel-Duby, Rhonda S; Olson, Eric N.

In: Science Advances, Vol. 5, No. 3, eaav4324, 01.01.2019.

Research output: Contribution to journalArticle

Min, YL, Li, H, Rodriguez-Caycedo, C, Mireault, AA, Huang, J, Shelton, JM, McAnally, JR, Amoasii, L, Mammen, PP, Bassel-Duby, RS & Olson, EN 2019, 'CRISPR-Cas9 corrects Duchenne muscular dystrophy exon 44 deletion mutations in mice and human cells', Science Advances, vol. 5, no. 3, eaav4324. https://doi.org/10.1126/sciadv.aav4324
Min YL, Li H, Rodriguez-Caycedo C, Mireault AA, Huang J, Shelton JM et al. CRISPR-Cas9 corrects Duchenne muscular dystrophy exon 44 deletion mutations in mice and human cells. Science Advances. 2019 Jan 1;5(3). eaav4324. https://doi.org/10.1126/sciadv.aav4324
Min, Yi Li ; Li, Hui ; Rodriguez-Caycedo, Cristina ; Mireault, Alex A. ; Huang, Jian ; Shelton, John M. ; McAnally, John R. ; Amoasii, Leonela ; Mammen, Pradeep P ; Bassel-Duby, Rhonda S ; Olson, Eric N. / CRISPR-Cas9 corrects Duchenne muscular dystrophy exon 44 deletion mutations in mice and human cells. In: Science Advances. 2019 ; Vol. 5, No. 3.
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