Data in support of: Atrophin-1 antisense oligonucleotide provides robust protection from pathology in a fully humanized DRPLA model
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2026
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| author | Carroll, Jeffery Smith, Velvet Gidi, Bereket |
| author_facet | Carroll, Jeffery Smith, Velvet Gidi, Bereket |
| contents | <p>Dentatorubral-pallidoluysian atrophy (DRPLA) is a fatal neurodegenerative disease arising from a CAG repeat expansion in the atrophin-1 (<em>ATN1</em>) gene. Because DRPLA, like many repeat expansion disorders (REDs), arises predominantly from toxic gain-of-function mechanisms, we hypothesized that <em>ATN1</em> 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 <em>Atn1</em> is completely replaced by human <em>ATN1</em>, 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 <em>Atn1<sup>Q112/+</sup></em> mouse—recapitulates key features of human DRPLA, including behavioral alterations, reduced brain size, and aggregate accumulation. We treated <em>Atn1<sup>Q112/+</sup></em> mice with antisense oligonucleotides (ASOs) targeting mouse <em>Atn1</em> (to probe for loss of function concerns), human <em>ATN1</em>, or a combination. Treatment with human, but not mouse, <em>ATN1</em>-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 <em>ATN1</em> for DRPLA.</p> |
| format | Recurso digital |
| id | zenodo_https___doi_org_10_5281_zenodo_18177006 |
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| publishDate | 2026 |
| publisher | Zenodo |
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| spellingShingle | Data in support of: Atrophin-1 antisense oligonucleotide provides robust protection from pathology in a fully humanized DRPLA model Carroll, Jeffery Smith, Velvet Gidi, Bereket DRPLA Mouse models Neurodegenerative diseases Antisense oligonucleotides <p>Dentatorubral-pallidoluysian atrophy (DRPLA) is a fatal neurodegenerative disease arising from a CAG repeat expansion in the atrophin-1 (<em>ATN1</em>) gene. Because DRPLA, like many repeat expansion disorders (REDs), arises predominantly from toxic gain-of-function mechanisms, we hypothesized that <em>ATN1</em> 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 <em>Atn1</em> is completely replaced by human <em>ATN1</em>, 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 <em>Atn1<sup>Q112/+</sup></em> mouse—recapitulates key features of human DRPLA, including behavioral alterations, reduced brain size, and aggregate accumulation. We treated <em>Atn1<sup>Q112/+</sup></em> mice with antisense oligonucleotides (ASOs) targeting mouse <em>Atn1</em> (to probe for loss of function concerns), human <em>ATN1</em>, or a combination. Treatment with human, but not mouse, <em>ATN1</em>-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 <em>ATN1</em> for DRPLA.</p> |
| title | Data in support of: Atrophin-1 antisense oligonucleotide provides robust protection from pathology in a fully humanized DRPLA model |
| topic | DRPLA Mouse models Neurodegenerative diseases Antisense oligonucleotides |
| url | https://doi.org/10.5281/zenodo.18177006 |