Cas9 nickase-mediated contraction of CAG/CTG repeats in vivo is accompanied by improvements in Huntington's disease pathology

Murillo Bartolome, Alvaro ORCID: https://orcid.org/0000-0001-5470-9347, Alpaugh, Melanie, Peter Durairaj, Ruban Rex, Randall, Emma L., Larin, Meghan, Heraty, Laura, Aston, Alys N., Taylor, Alysha S., Mas Monteys, Alex, Stoberl, Nina, Heuchan, Aeverie E. R., Aeschlimann, Pascale, Fears, Kyle, Landles, Christian, Osborne, Georgina F., Mangin, Antoine, Bhattacharyya, Soumyasree, Metzakopian, Emmanouil, Allen, Nicholas D. ORCID: https://orcid.org/0000-0003-4009-186X, Puymirat, Jack, Bates, Gillian P., Davidson, Beverly L., Cicchetti, Francesca, Lelos, Mariah J. ORCID: https://orcid.org/0000-0001-7102-055X and Dion, Vincent ORCID: https://orcid.org/0000-0003-4953-7637 2026. Cas9 nickase-mediated contraction of CAG/CTG repeats in vivo is accompanied by improvements in Huntington's disease pathology. Science Translational Medicine 18 (872) 10.1126/scitranslmed.aef9466

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Abstract

Expanded CAG/CTG repeats cause more than 15 different diseases that all remain without a disease-modifying treatment. Because repeat length accounts for most of the variation in disease severity, contracting CAG/CTG repeats presents an attractive therapeutic avenue. Here, we show that the CRISPR-Cas9 nickase targeted to CAG/CTG repeats leads to efficient repeat contractions in Huntington’s disease (HD) patient–derived neurons and astrocytes and in myotonic dystrophy type 1 patient–derived neurons. The approach was allele selective and free of detectable off-target mutations. Injection of the Cas9 nickase into the striatum of the R6/1 mouse model of HD using adeno-associated viral vectors led to repeat contractions in more than half of striatal neurons. Upon injection, we observed a reduction in the number of inclusion bodies, an improved gene expression profile, and amelioration of locomotion deficits in the open field test. The effects were greater than expected from the contractions induced, suggesting that non–cell autonomous mechanisms may be involved. Our results provide the proof of concept that correction of CAG/CTG repeats can improve HD phenotypes in a mouse disease model.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine Schools > Biosciences
Additional Information:	RRS applied
Publisher:	American Association for the Advancement of Science
ISSN:	1946-6234
Funders:	UK Dementia Research Institute, UK Medical Research Council
Date of First Compliant Deposit:	15 October 2026
Date of Acceptance:	23 September 2026
Last Modified:	30 Oct 2026 11:15
URI:	https://orca.cardiff.ac.uk/id/eprint/190241

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