Data in support of: 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 (ATN1) gene.
Because DRPLA, like many repeat expansion disorders (REDs), arises
predominantly from toxic gain-of-function mechanisms, we hypothesized that
ATN1 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 Atn1 is completely replaced by human ATN1, 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 Atn1Q112/+
mouse—recapitulates key features of human DRPLA, including behavioral
alterations, reduced brain size, and aggregate accumulation. We treated
Atn1Q112/+ mice with antisense oligonucleotides (ASOs) targeting mouse
Atn1 (to probe for loss of function concerns), human ATN1, or a
combination. Treatment with human, but not mouse, ATN1-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 ATN1 for DRPLA.