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.…
A humanized mouse model of Dentatorubral-pallidoluysian atrophy (DRPLA) has been developed to study the effects of a disease-causing mutation on epilepsy. DRPLA is a rare genetic disorder caused by an abnormal expansion of CAG repeats in the atrophin-1 (ATN1) gene, leading to progressive myoclonus epilepsy. In this study, researchers engineered an ATN1 mouse with 112 CAG repeats, mimicking the human disease, and compared it to wild-type mice.
The Atn1Q112/+ mice exhibited higher seizure susceptibility, early death, and ataxia compared to the WT mice. However, when treated with an experimental antisense oligonucleotide (ASO) targeting the human, CAG-expanded ATN1 gene, the seizure threshold was normalized, ataxia was reduced, and early death was prevented. The ASO-treated mice also showed improvement in seizure-related brain wave patterns (EEG) and behavioral seizures.
These findings suggest that the ATN1 mouse model is a valuable tool for studying DRPLA epilepsy and could potentially be used to investigate new therapeutic approaches for this rare and debilitating condition.
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