Cas9 nickase-mediated contraction of CAG/CTG repeats is associated with phenotypic improvements in a Huntington's disease mouse model.

Cas9 nickase targeting CAG/CTG repeats induces repeat contractions in HD models and improves phenotypes in a mouse model, with over 50% of striatal neurons affected.

• Why it matters: Expanded CAG/CTG repeats are linked to over 15 diseases, with repeat length explaining most of the variation in disease severity, highlighting the need for targeted therapies.
• What they did: The study used CRISPR-Cas9 nickase to selectively contract repeats in patient-derived neurons, astrocytes, and in vivo mouse striatal neurons, achieving allele specificity without off-target mutations.
• The result: Repeat contractions correlated with reduced inclusion bodies, improved gene expression, and better locomotion, indicating potential for disease modification through repeat correction.