PT  - JOURNAL ARTICLE
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
TI  - CRISPR-Cas9 targeted deletion of the <em>C9orf72</em> repeat expansion mutation corrects cellular phenotypes in patient-derived iPS cells
AID  - 10.1101/051193
DP  - 2016 Jan 01
TA  - bioRxiv
PG  - 051193
4099  - http://biorxiv.org/content/early/2016/05/02/051193.short
4100  - http://biorxiv.org/content/early/2016/05/02/051193.full
AB  - 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.