Antisense oligonucleotide therapy rescues disturbed brain rhythms and sleep in juvenile and adult mouse models of Angelman syndrome
- Baylor College of Medicine, United States
- Ionis Pharmaceuticals, United States
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 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 electroencephalogram power spectrum and sleep architecture should be used to evaluate the clinical efficacy of therapies.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figure 3, Figure 3-supplement 1, Figure 3-supplement 3, and Figure 3-supplement 4.
Article and author information
Author details
Funding
Texas Children's Hospital (Main Street America Fund)
- Mingshan Xue
National Institute of Neurological Disorders and Stroke (R01NS100893)
- Mingshan Xue
National Institute of Mental Health (R01MH117089)
- Mingshan Xue
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (AN-6544) of Baylor College of Medicine.
Copyright
© 2023, Lee et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Antisense oligonucleotide therapy rescues disturbed brain rhythms and sleep in juvenile and adult mouse models of Angelman syndrome
eLife 12:e81892.
https://doi.org/10.7554/eLife.81892
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