Gene correction as a therapy for frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) caused by the C9orf72 mutation

Claire Clelland, MD, PhD University of California


Bruce Conklin, MD University of California, San Francisco and the Gladstone Institutes
Li Gan, PhD Weil Cornell Medicine


Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two fatal and incurable neurodegenerative diseases linked by a shared genetic cause – a heterozygous hexanucleotide (GGGGCC) repeat expansion in a single allele of the C9orf72 gene. The goal of this work is to develop novel CRISPR based therapeutic gene editing technologies and test whether gene editing can reverse the cellular pathology caused by this repeat expansion in patient derived cells. The results of these studies will advance our use of CRISPR technologies for therapeutic editing in FTD/ALS, inform our understanding of the regulation of C9orf72 gene, and will be applicable to many other repeat expansion and single gene disorders.

Project Details

Dr. Clelland and her team are applying new CRISPR and sequencing technologies to better understand how the repeat expansion of the C9orf72 gene causes disease. C9orf72 is the leading known genetic cause of both frontotemporal dementia (FTD) and ALS. The mutation in the C9orf72 gene is an expansion of GGGGCC, repeated hundreds or thousands of times, in the non-coding 5' end of the gene. Currently, methods to accurately size the repeat expansion are limited. We are using CRISPR and single molecule sequencing through Pacific Biosciences (PacBio) to generate new methods to accurately size the repeat expansion and quantify it across human induced pluripotent stem cell (iPSC) lines and human tissues. Our goal is to develop a better understanding of how this gene mutation functions and causes disease.