Atrophin-1 antisense oligonucleotide provides robust protection from pathology in a fully humanized DRPLA model

Dentatorubral-pallidoluysian atrophy (DRPLA) is a fatal neurodegenerative disease arising from a CAG repeat expansion in the atrophin-1 (<i>ATN1</i>) gene. Because DRPLA, like many repeat expansion disorders (REDs), arises predominantly from toxic gain-of-function mechanisms, we hypothesized that <i>ATN1</i> 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 <i>Atn1</i> is completely replaced by human <i>ATN1</i>, 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 <i>Atn1</i> ^{<i>Q112/+</i>} mouse-recapitulates key features of human DRPLA, including behavioral alterations, reduced brain size, and aggregate accumulation. We treated <i>Atn1</i> ^{<i>Q112/+</i>} mice with antisense oligonucleotides (ASOs) targeting mouse <i>Atn1</i> (to probe for loss of function concerns), human <i>ATN1</i>, or a combination. Treatment with human, but not mouse, <i>ATN1</i>-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 <i>ATN1</i> for DRPLA.