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Spell Checking Nature: Versatility of CRISPR/Cas9 for Developing Treatments for Inherited Disorders

2015; Elsevier BV; Volume: 98; Issue: 1 Linguagem: Inglês

10.1016/j.ajhg.2015.11.012

1537-6605

Daria Wojtal, Dwi U. Kemaladewi, Zeenat Malam, Sarah Abdullah, Tatianna Wai Ying Wong, Elzbieta Hyatt, Zahra Baghestani, Sérgio L. Pereira, James Stavropoulos, Vincent Mouly, Kamel Mamchaoui, Francesco Muntoni, Thomas Voit, Hernán Gonorazky, James J. Dowling, Michael D. Wilson, Roberto Mendoza‐Londono, Evgueni A. Ivakine, Ronald D. Cohn,

Innovation and Socioeconomic Development

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/Cas9, which can be tailored to target numerous inherited disorders.