Science translational medicineOct 22, 2026

Reducing repeated DNA sections with Cas9 nickase is linked to symptom improvements in a Huntington’s disease mouse model

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 23, 2026

Abstract

CRISPR-Cas9 nickase targeted to CAG/CTG repeats led to repeat contractions in more than half of striatal neurons in a mouse model of Huntington's disease.

Contracting CAG/CTG repeats may reduce disease severity in Huntington's disease and myotonic dystrophy type 1.
The CRISPR-Cas9 approach was allele selective and resulted in no detectable off-target mutations.
Injection into the striatum resulted in a reduction of inclusion bodies and an improved gene expression profile.
Observed locomotion deficits in the open field test were ameliorated following treatment.
Effects exceeded expectations based on the degree of repeat contractions, suggesting possible involvement of non-cell autonomous mechanisms.

Simplified

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.

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Reducing repeated DNA sections with Cas9 nickase is linked to symptom improvements in a Huntington’s disease mouse model

Abstract

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