biostudies-literatureUnknown37(1)Smith VLDentatorubral-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>AtMolecular therapy. Nucleic acids102815https://www.ebi.ac.uk/biostudies/studies/S-EPMC12857545biostudies-literatureAtrophin-1 antisense oligonucleotide provides robust protection from pathology in a fully humanized DRPLA model.PMC12857545Greenfield JBen-Varon AKhurana VZhao HTBarker-Haliski MChild DDCarroll JBGidi BZCompton ACantle JPKordasiewicz HBYu TSmith VLNoble BGemos APrades SBragg RMKorecka JAfalseAtrophin-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>At2026-01-01T00:00:00Z2026 Mar2026-06-18T05:48:05.49Z2026-06-18T03:07:30.357ZS-EPMC128575454162433210.1016/j.omtn.2025.102815