Antisense Oligonucleotide Therapy Rescues Disturbed Brain Rhythms and Sleep in Juvenile and Adult Mouse Models of Angelman Syndrome

Authors

Dongwon Lee
Wu Chen
Heet Naresh Kaku
Xinming Zhuo
Eugene S Chao
Armand Soriano
Allen Kuncheria
Stephanie Flores
Joo Hyun Kim
Armando Rivera
Frank Rigo
Paymaan Jafar-Nejad
Arthur L Beaudet
Matthew S Caudill
Mingshan Xue

Publication Date

1-3-2023

Journal

eLife

DOI

10.7554/eLife.81892

PMID

36594817

PMCID

PMC9904759

PubMedCentral® Posted Date

1-3-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Mice, Animals, Angelman Syndrome, Brain, Oligonucleotides, Antisense, Mice, Knockout, Sleep, Ubiquitin-Protein Ligases, Disease Models, Animal

Abstract

UBE3A encodes ubiquitin protein ligase E3A, and in neurons its expression from the paternal allele is repressed by the UBE3A antisense transcript (UBE3A-ATS). This leaves neurons susceptible to loss-of-function of maternal UBE3A. Indeed, Angelman syndrome, a severe neurodevelopmental disorder, is caused by maternal UBE3A deficiency. A promising therapeutic approach to treating Angelman syndrome is to reactivate the intact paternal UBE3A by suppressing UBE3A-ATS. Prior studies show that many neurological phenotypes of maternal Ube3a knockout mice can only be rescued by reinstating Ube3a expression in early development, indicating a restricted therapeutic window for Angelman syndrome. Here, we report that reducing Ube3a-ATS by antisense oligonucleotides in juvenile or adult maternal Ube3a knockout mice rescues the abnormal electroencephalogram (EEG) rhythms and sleep disturbance, two prominent clinical features of Angelman syndrome. Importantly, the degree of phenotypic improvement correlates with the increase of Ube3a protein levels. These results indicate that the therapeutic window of genetic therapies for Angelman syndrome is broader than previously thought, and EEG power spectrum and sleep architecture should be used to evaluate the clinical efficacy of therapies.