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

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.