Gorde:
| Egile Nagusiak: | , , |
|---|---|
| Formatua: | Recurso digital |
| Hizkuntza: | |
| Argitaratua: |
Zenodo
2026
|
| Gaiak: | |
| Sarrera elektronikoa: | https://doi.org/10.5281/zenodo.18177006 |
| Etiketak: |
Etiketa erantsi
Etiketarik gabe, Izan zaitez lehena erregistro honi etiketa jartzen!
|
Aurkibidea:
- <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>