A Humanized Mouse Model of DRPLA Recapitulates Epilepsy and Demonstrates Antisense Oligonucleotide-Mediated Disease Modification

WU, Q.; Erickson, I.; Davidson, S.; Shonka, S.; Smith, V.; Gidi, B.; Knox, K.; Yu, T. W.; Khurana, V.; Carroll, J.; Korecka, J. A.; Barker-Haliski, M.

doi:10.64898/2026.10.12.758592

bioRxiv · 10.64898/2026.10.12.758592

A Humanized Mouse Model of DRPLA Recapitulates Epilepsy and Demonstrates Antisense Oligonucleotide-Mediated Disease Modification

WU, Q.·Erickson, I.·Davidson, S.·Shonka, S.·Smith, V.·Gidi, B.·Knox, K.·Yu, T. W.·Khurana, V.·Carroll, J.·Korecka, J. A.·Barker-Haliski, M.

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Abstract

Dentatorubral-pallidoluysian atrophy (DRPLA) is an ultra-rare progressive myoclonus epilepsy caused by a glutamine-coding CAG repeat expansion in atrophin-1 (ATN1). Mutant ATN1 (mATN1) expression results in symptoms that inversely correlate to CAG-expansion size: young-onset cases have the most CAG repeats and developmental delay, high-frequency treatment-resistant seizures, and early mortality. We sought to characterize the seizure susceptibility of a fully humanized ATN1 mouse expressing human mATN1 with 112 CAG repeats to then assess therapeutic antisense oligonucleotide (ASO) intervention on seizure-related outcomes. Atn1Q112/+ or wild-type (WT) mice were treated with investigational ASO targeting human, CAG-expanded, ATN1 or saline (P2 and then again at 4 weeks-old) before acute seizure testing, ataxia profiling, and chronic in vivo video-EEG recording for spontaneous seizures up to 8 weeks-old. Saline-treated Atn1Q112/+ mice were more seizure prone with early death. However, ASO administration to Atn1Q112/+ mice normalized seizure threshold, decreased ataxia, and protected against early death. Atn1Q112/+ mice exhibited spontaneous behavioral seizures recorded over 2 weeks, which were absent in ASO-treated Atn1Q112/+ and WT mice, with a specific mATN1 expression-driven decrease in delta and theta EEG frequencies. Atn1Q112/+ mice are highly seizure prone, validating this model for DRPLA epilepsy. ATN1 represents a novel epilepsy-related risk factor for therapeutic investigation.

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WU, Q., Erickson, I., Davidson, S., Shonka, S., Smith, V., Gidi, B., Knox, K., Yu, T. W., Khurana, V., Carroll, J., Korecka, J. A., Barker-Haliski, M.. 2026-10-18. A Humanized Mouse Model of DRPLA Recapitulates Epilepsy and Demonstrates Antisense Oligonucleotide-Mediated Disease Modification. https://doi.org/10.64898/2026.10.12.758592

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