Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 98, Issue 1, Pages 90-101Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2015.11.012
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Funding
- SickKids Restracomp and Eric Hani Fellowship
- AFM-Telethon
- Cure CMD
- Natural Sciences and Engineering Research Council Canada Research Chair [436194-2013]
- Duchenne Children's Trust
- Women's Auxiliary of the The Hospital for Sick Children (Chair in Clinical and Metabolic Genetics)
- SickKids Foundation
- Medical Research Council [MR/K000608/1] Funding Source: researchfish
- Muscular Dystrophy UK [RA2/3076] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0515-10022] Funding Source: researchfish
- MRC [MR/K000608/1] Funding Source: UKRI
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Clustered regularly interspaced short palindromic repeat (CRISPR) has arisen as a frontrunner for efficient genome engineering. However, the potentially broad therapeutic implications are largely unexplored. Here, to investigate the therapeutic potential of CRISPR/Cas9 in a diverse set of genetic disorders, we establish a pipeline that uses readily obtainable cells from affected individuals. We show that an adapted version of CRISPR/Cas9 increases the amount of utrophin, a known disease modifier in Duchenne muscular dystrophy (DMD). Furthermore, we demonstrate preferential elimination of the dominant-negative FGFR3 c.1138G>A allele in fibroblasts of an individual affected by achondroplasia. Using a previously undescribed approach involving single guide RNA, we successfully removed large genome rearrangement in primary cells of an individual with an X chromosome duplication including MECP2. Moreover, removal of a duplication of DMD exons 18-30 in myotubes of an individual affected by DMD produced full-length dystrophin. Our findings establish the far-reaching therapeutic utility of CRISPR/Ca59, which can be tailored to target numerous inherited disorders.
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