Authors :
Presenting Author: Melissa Barker-Haliski, PhD – University of Washington
Qian Wu, MD, PhD – University of Washington
Kevin Knox, BS – University of Washington
Velvet Smith, BS – University of Washington
Bereket Gidi, BS – University of Washington
Seongheon Rho, BS – University of Washington
Tim Yu, MD, PhD – Harvard Medical School
Vikram Khurana, MD, PhD – MassGeneral Brigham, Harvard Medical School
Jeff Carroll, PhD – University of Washington
Joanna Koerecka-Roet, PhD – Brigham and Women's Hospital, Harvard Medical School
Rationale: Dentatorubral-pallidoluysian atrophy (DRPLA) is an ultra-rare neurodegenerative disease and progressive myoclonus epilepsy caused by expansion of a glutamine-coding CAG repeat in the Atrophin-1 (
Atn1) gene. The role of
Atn1 is currently unknown. However, the clinical manifestations of
Atn1 overexpression leads to a constellation of symptoms that are inversely correlated to CAG-expansion size, with younger individuals typically carrying the largest number of CAG repeats and having the most severe disease burden. Importantly, young patients with DRPLA experience poor long-term outcomes, including developmental delay, high-frequency treatment-resistant seizures, and high mortality. Thus,
Atn1 represents a novel and unstudied risk factor that increases seizure susceptibility, worsens seizure-related outcomes, and promotes premature mortality. Our present goal was to implement a novel humanized mouse model of
Atn1 overexpression to assess the disease-modifying effect of therapeutic antisense oligonucleotide (ASO) intervention on seizure presentation and seizure-related long-term outcomes.
Methods: We characterized the seizure phenotype of a novel transgenic
Atn1 humanized mouse to establish the suitability of this model for future precision medicine discoveries in epilepsy, as well as to expand our understanding of the contributions that
Atn1 and CAG-repeat expansion disorders can have on seizure risk in early life. Male and female
Atn1-Q112 or wild-type (WT) mice (n=9-15/group) were treated with an investigational ASO or saline on P2 and then again at 5 weeks (intracerebralventricular injection) before undergoing minimal clonic seizure threshold screening, in vivo EEG recording for potential spontaneous recurrent seizures, and circadian behaviors at 8 weeks old. WT and
Atn1-variant mice (n=4-6/group) were video-EEG monitored for potential spontaneous seizure activity commencing at 5-6 weeks of age.
Results:
Atn1-Q112 mice treated with and without the investigational ASO exhibited significant shifts in the post-electrical stimulation seizure phenotype as a result of Atn1 mutation, leading to significant increases in the perceived seizure threshold of untreated mice likely due to an ataxia phenotype (Fig 1). However, the administration of the investigational ASO to Atn1-Q112 mice normalized seizure threshold relative to saline-treated WT mice. There were beneficial improvements in several innate behaviors of Atn1-Q112 mice that received the ASO over the 72-hour behavioral monitoring period, including reduced home cage hyperlocomotion (Fig 2). Spontaneous recurrent seizure burden via video-EEG monitoring will be further discussed as data acquisition and review is still ongoing.
Conclusions: This study establishes a novel role of
Atn1 and related CAG-repeat expansion disorders in seizure susceptibility. It also provides a previously untapped precision medicine discovery strategy for DRPLA, as well as more broadly uncovers novel seizure-related risk factors and therapeutic targets for other ultra-rare progressive myoclonus epilepsies and seizure disorders.
Funding: This work was supported by Cure DRPLA and a 2024 American Epilepsy Society Seed Grant.