Cas9 nickase shortens CAG repeats and eases Huntington's signs in mice
- A Cas9 nickase aimed at CAG/CTG repeats induces contraction of the repeat length that drives severity in Huntington's and related disorders.
- It worked in patient-derived neurons and astrocytes (Huntington's, myotonic dystrophy), favouring the expanded allele without detected off-target mutations.
- In R6/1 mice, striatal AAV delivery shortened repeats, cut inclusion bodies and improved gene expression and locomotion, more than contraction predicts, hinting at non-cell-autonomous effects.
💡 Points
The benefit that outruns what contraction predicts is the most interesting result here, and the least secure. In a fast, fragment-transgene model like R6/1 it could just as easily reflect nickase or AAV expression effects, so a catalytically dead control and a full-length knock-in would settle more than another efficacy readout. Long-term nick-related toxicity and spread beyond the striatum also need data.