Dual-targeting CRISPR-CasRx reduces C9orf72 ALS/FTD sense and antisense repeat RNAs in vitro and in vivo

Liam Kempthorne, Deniz Vaizoglu, Alexander J. Cammack, Mireia Carcolé, Martha J. Roberts, Alla Mikheenko, Alessia Fisher, Pacharaporn Suklai, Bhavana Muralidharan, François Kroll, Thomas G. Moens, Lidia Yshii, Stijn Verschoren, Benedikt V. Hölbling, Francisco C. Moreira, Eszter Katona, Rachel Coneys, Paula Oliveira, Yong-Jie Zhang, Karen Jansen, Lillian M. Daughrity, Alexander McGown, Tennore M. Ramesh, Ludo Bosch, Gabriele Lignani, Ahad A. Rahim, Alyssa N. Coyne, Leonard Petrucelli, Jason Rihel and Adrian M. Isaacs ()
Additional contact information
Liam Kempthorne: UK Dementia Research Institute at UCL
Deniz Vaizoglu: UK Dementia Research Institute at UCL
Alexander J. Cammack: UK Dementia Research Institute at UCL
Mireia Carcolé: UK Dementia Research Institute at UCL
Martha J. Roberts: UK Dementia Research Institute at UCL
Alla Mikheenko: UK Dementia Research Institute at UCL
Alessia Fisher: UK Dementia Research Institute at UCL
Pacharaporn Suklai: UK Dementia Research Institute at UCL
Bhavana Muralidharan: UK Dementia Research Institute at UCL
François Kroll: University College London
Thomas G. Moens: VIB-KU Center for Brain and Disease Research
Lidia Yshii: VIB-KU Center for Brain and Disease Research
Stijn Verschoren: VIB-KU Center for Brain and Disease Research
Benedikt V. Hölbling: UK Dementia Research Institute at UCL
Francisco C. Moreira: UCL Queen Square Institute of Neurology
Eszter Katona: UK Dementia Research Institute at UCL
Rachel Coneys: UK Dementia Research Institute at UCL
Paula Oliveira: UK Dementia Research Institute at UCL
Yong-Jie Zhang: Mayo Clinic
Karen Jansen: Mayo Clinic
Lillian M. Daughrity: Mayo Clinic
Alexander McGown: University of Sheffield
Tennore M. Ramesh: University of Sheffield
Ludo Bosch: VIB-KU Center for Brain and Disease Research
Gabriele Lignani: UCL Queen Square Institute of Neurology
Ahad A. Rahim: University College London
Alyssa N. Coyne: Johns Hopkins University
Leonard Petrucelli: Mayo Clinic
Jason Rihel: University College London
Adrian M. Isaacs: UK Dementia Research Institute at UCL

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: Abstract The most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is an intronic G4C2 repeat expansion in C9orf72. The repeats undergo bidirectional transcription to produce sense and antisense repeat RNA species, which are translated into dipeptide repeat proteins (DPRs). As toxicity has been associated with both sense and antisense repeat-derived RNA and DPRs, targeting both strands may provide the most effective therapeutic strategy. CRISPR-Cas13 systems mature their own guide arrays, allowing targeting of multiple RNA species from a single construct. We show CRISPR-Cas13d variant CasRx effectively reduces overexpressed C9orf72 sense and antisense repeat transcripts and DPRs in HEK cells. In C9orf72 patient-derived iPSC-neuron lines, CRISPR-CasRx reduces endogenous sense and antisense repeat RNAs and DPRs and protects against glutamate-induced excitotoxicity. AAV delivery of CRISPR-CasRx to two distinct C9orf72 repeat mouse models significantly reduced both sense and antisense repeat-containing transcripts. This highlights the potential of RNA-targeting CRISPR systems as therapeutics for C9orf72 ALS/FTD.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-55550-x Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55550-x

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-55550-x

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().