First fully humanized mouse model of a repeat expansion disorder (RED), specifically DRPLA, with one allele of mouse Atn1 replaced by human ATN1 with 112 CAG repeats.

Antisense oligonucleotides (ASOs) targeting human ATN1, but not mouse Atn1, showed remarkable protection from disease-related behavioral phenotypes and rescued transcriptional dysregulation in the cerebellum.

Results from the mouse model support the ongoing human clinical study of ATN1-targeting ASOs for DRPLA treatment.