CRISPR/Cas9-mediated excision of ALS/FTD-causing hexanucleotide repeat expansion in C9ORF72 rescues major disease mechanisms in vivo and in vitro

Katharina E. Meijboom, Abbas Abdallah, Nicholas P. Fordham, Hiroko Nagase, Tomás Rodriguez, Carolyn Kraus, Tania F. Gendron, Gopinath Krishnan, Rustam Esanov, Nadja S. Andrade, Matthew J. Rybin, Melina Ramic, Zachary D. Stephens, Alireza Edraki, Meghan T. Blackwood, Aydan Kahriman, Nils Henninger, Jean-Pierre A. Kocher, Michael Benatar, Michael H. Brodsky, Leonard Petrucelli, Fen-Biao Gao, Erik J. Sontheimer, Robert H. Brown, Zane Zeier () and Christian Mueller ()
Additional contact information
Katharina E. Meijboom: University of Massachusetts Medical School
Abbas Abdallah: University of Massachusetts Medical School
Nicholas P. Fordham: University of Massachusetts Medical School
Hiroko Nagase: University of Massachusetts Medical School
Tomás Rodriguez: University of Massachusetts Medical School
Carolyn Kraus: University of Massachusetts Medical School
Tania F. Gendron: Department of Neuroscience, Mayo Clinic
Gopinath Krishnan: University of Massachusetts Medical School
Rustam Esanov: University of Miami Miller School of Medicine
Nadja S. Andrade: University of Miami Miller School of Medicine
Matthew J. Rybin: University of Miami Miller School of Medicine
Melina Ramic: University of Miami Miller School of Medicine
Zachary D. Stephens: Department of Quantitative Health Sciences. Mayo Clinic
Alireza Edraki: University of Massachusetts Medical School
Meghan T. Blackwood: University of Massachusetts Medical School
Aydan Kahriman: University of Massachusetts Medical School
Nils Henninger: University of Massachusetts Medical School
Jean-Pierre A. Kocher: Department of Quantitative Health Sciences. Mayo Clinic
Michael Benatar: University of Miami Miller School of Medicine
Michael H. Brodsky: University of Massachusetts Medical School
Leonard Petrucelli: Department of Neuroscience, Mayo Clinic
Fen-Biao Gao: University of Massachusetts Medical School
Erik J. Sontheimer: University of Massachusetts Medical School
Robert H. Brown: University of Massachusetts Medical School
Zane Zeier: University of Miami Miller School of Medicine
Christian Mueller: University of Massachusetts Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract A GGGGCC24+ hexanucleotide repeat expansion (HRE) in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), fatal neurodegenerative diseases with no cure or approved treatments that substantially slow disease progression or extend survival. Mechanistic underpinnings of neuronal death include C9ORF72 haploinsufficiency, sequestration of RNA-binding proteins in the nucleus, and production of dipeptide repeat proteins. Here, we used an adeno-associated viral vector system to deliver CRISPR/Cas9 gene-editing machineries to effectuate the removal of the HRE from the C9ORF72 genomic locus. We demonstrate successful excision of the HRE in primary cortical neurons and brains of three mouse models containing the expansion (500–600 repeats) as well as in patient-derived iPSC motor neurons and brain organoids (450 repeats). This resulted in a reduction of RNA foci, poly-dipeptides and haploinsufficiency, major hallmarks of C9-ALS/FTD, making this a promising therapeutic approach to these diseases.

Date: 2022
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DOI: 10.1038/s41467-022-33332-7

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