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Dentatorubral-pallidoluysian atrophy (DRPLA) is a fatal neurodegenerative disease arising from a CAG repeat expansion in the atrophin-1 () gene. Because DRPLA, like many repeat expansion disorders (REDs), arises predominantly from toxic gain-of-function mechanisms, we hypothesized that knockdown would have therapeutic potential. To test this, we established the first fully humanized mouse model of a RED, in which one allele of mouse is completely replaced by human , including 112 pure CAG repeats. This novel approach to exploring RED biology provides significant advantages, notably the ability to test sequence-specific therapeutics targeting human sequences, even in introns and untranslated regions of pre-mRNA. We found that our model-the mouse-recapitulates key features of human DRPLA, including behavioral alterations, reduced brain size, and aggregate accumulation. We treated mice with antisense oligonucleotides (ASOs) targeting mouse (to probe for loss of function concerns), human , or a combination. Treatment with human, but not mouse, -targeting ASOs provides remarkable protection from a range of disease-related behavioral phenotypes and marked rescue of transcriptional dysregulation in the cerebellum. These results have helped motivate an ongoing human clinical study of ASOs targeting for DRPLA.