TY - JOUR T1 - CRISPR-Cas9 targeted deletion of the <em>C9orf72</em> repeat expansion mutation corrects cellular phenotypes in patient-derived iPS cells JF - bioRxiv DO - 10.1101/051193 SP - 051193 AU - Mochtar Pribadi AU - Zhongan Yang AU - Tanya S. Kim AU - Elliot W. Swartz AU - Alden Y. Huang AU - Jason A. Chen AU - Deepika Dokuru AU - Jaeyun Baek AU - Fuying Gao AU - Andrea T. Fua AU - Kevin Wojta AU - Qing Wang AU - Anna Karydas AU - Jamie Fong AU - Ed Lezcano AU - Stephanie Ng AU - Farid F. Chehab AU - Harry V. Vinters AU - Bruce L. Miller AU - Giovanni Coppola Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/05/02/051193.abstract N2 - The large hexanucleotide (GGGGCC) repeat expansion in the non-coding promoter region of C9orf72 is the leading cause of Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). Mechanisms underlying neurodegeneration are not clear, and both a C9orf72 loss of function and a gain of toxicity, in the form of RNA foci or dipeptide repeat deposition, are implicated. CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9-mediated genome editing is an attractive strategy for disease modeling and therapeutic intervention. Here we show that this system can be utilized to completely remove the large repeat expansion mutation within C9orf72 in patient-derived induced pluripotent stem (iPS) cells. Removal of the mutation prevented RNA foci formation and promoter hypermethylation, two phenotypes of the C9orf72 mutation. Interestingly, these changes did not significantly alter C9orf72 expression at the mRNA or protein level. This work provides a proof-of-principle for the use of CRISPR-Cas9-mediated excision of the pathogenic C9orf72 repeat expansion as a therapeutic strategy in FTD/ALS.One Sentence Summary CRISPR-Cas9-mediated excision of the large C9orf72 repeat expansion mutation rescues RNA foci formation and promoter hypermethylation without altering C9orf72 transcript and protein expression. ER -