A high-fidelity CRISPR-Cas13 system improves abnormalities associated with C9ORF72-linked ALS/FTD

Tristan X. McCallister, Colin K. W. Lim, Mayuri Singh, Sijia Zhang, Najah S. Ahsan, William M. Terpstra, Alisha Y. Xiong, M. Alejandra Zeballos C, Jackson E. Powell, Jenny Drnevich, Yifei Kang and Thomas Gaj ()
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Tristan X. McCallister: University of Illinois Urbana-Champaign
Colin K. W. Lim: University of Illinois Urbana-Champaign
Mayuri Singh: University of Illinois Urbana-Champaign
Sijia Zhang: University of Illinois Urbana-Champaign
Najah S. Ahsan: University of Illinois Urbana-Champaign
William M. Terpstra: University of Illinois Urbana-Champaign
Alisha Y. Xiong: University of Illinois Urbana-Champaign
M. Alejandra Zeballos C: University of Illinois Urbana-Champaign
Jackson E. Powell: University of Illinois Urbana-Champaign
Jenny Drnevich: University of Illinois Urbana-Champaign
Yifei Kang: University of Illinois Urbana-Champaign
Thomas Gaj: University of Illinois Urbana-Champaign

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract An abnormal expansion of a GGGGCC (G4C2) hexanucleotide repeat in the C9ORF72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two debilitating neurodegenerative disorders driven in part by gain-of-function mechanisms involving transcribed forms of the repeat expansion. By utilizing a Cas13 variant with reduced collateral effects, we develop here a high-fidelity RNA-targeting CRISPR-based system for C9ORF72-linked ALS/FTD. When delivered to the brain of a transgenic rodent model, this Cas13-based platform curbed the expression of the G4C2 repeat-containing RNA without affecting normal C9ORF72 levels, which in turn decreased the formation of RNA foci, reduced the production of a dipeptide repeat protein, and reversed transcriptional deficits. This high-fidelity system possessed improved transcriptome-wide specificity compared to its native form and mediated targeting in motor neuron-like cells derived from a patient with ALS. These results lay the foundation for the implementation of RNA-targeting CRISPR technologies for C9ORF72-linked ALS/FTD.

Date: 2025
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DOI: 10.1038/s41467-024-55548-5

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