Summary
A bioRxiv preprint reports that an antisense oligonucleotide targeting expanded human ATN1 improved seizure-related outcomes in a humanized mouse model of DRPLA. The findings come from mice, not a human treatment study.
A preprint describes a humanized mouse model of dentatorubral-pallidoluysian atrophy (DRPLA) that developed seizure susceptibility and spontaneous behavioral seizures. In the same model, an investigational antisense oligonucleotide (ASO) targeting expanded human ATN1 improved several seizure-related outcomes, reduced ataxia and protected against early death, the researchers report.
The study, posted on bioRxiv, tested mice carrying one copy of human ATN1 with 112 CAG repeats, designated Atn1Q112/+. DRPLA is an ultra-rare, progressive neurological disorder associated with CAG-repeat expansion in ATN1. CAG is a DNA sequence that encodes the amino acid glutamine; in DRPLA, the expanded repeat leads to mutant atrophin-1.
Testing seizure susceptibility and treatment
Researchers treated the mutant mice with either an investigational ASO designed to target human expanded ATN1 or saline. The animals received treatment at postnatal day 2 and again at four weeks of age. Wild-type mice were also included for comparison. The team assessed acute seizure responses, ataxia and spontaneous seizures using video-electroencephalography (video-EEG), with monitoring extending to eight weeks of age.
Saline-treated Atn1Q112/+ mice were more seizure-prone and had early deaths. The researchers report that ASO treatment normalized seizure threshold, decreased ataxia and protected against early death. During a two-week period of video-EEG recording, spontaneous behavioral seizures occurred in mutant mice but were absent in ASO-treated mutant mice and wild-type controls.
The recordings also showed lower delta- and theta-frequency EEG activity associated with mutant ATN1 expression. These findings add electrophysiological measures to the seizure and movement-related features observed in the model.
The results make the model useful for studying how expanded ATN1 contributes to epilepsy-related features in DRPLA and for investigating treatments aimed at the disease-associated gene. The ASO findings are preclinical: the study tested mice, and the treatment remains investigational. The preprint reports no human treatment outcomes.