Antisense oligonucleotide therapy rescues disturbed brain rhythms and sleep in juvenile and adult mouse models of Angelman syndrome

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

  1. Dongwon Lee

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  2. Wu Chen

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    For correspondence
    wu.chen@bcm.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7400-0519
  3. Heet Naresh Kaku

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  4. Xinming Zhuo

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  5. Eugene S Chao

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  6. Armand Soriano

    Ionis Pharmaceuticals, Carlsbad, United States
    Competing interests
    Armand Soriano, is a paid employee of Ionis Pharmaceuticals..
  7. Allen Kuncheria

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  8. Stephanie Flores

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  9. Joo Hyun Kim

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  10. Armando Rivera

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7076-8566
  11. Frank Rigo

    Ionis Pharmaceuticals, Carlsbad, United States
    Competing interests
    Frank Rigo, is a paid employee of Ionis Pharmaceuticals..
  12. Paymaan Jafar-nejad

    Ionis Pharmaceuticals, Carlsbad, United States
    Competing interests
    Paymaan Jafar-nejad, is a paid employee of Ionis Pharmaceuticals..
  13. Arthur L Beaudet

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    Arthur L Beaudet, is a paid employee of Luna Genetics..
  14. Matthew S Caudill

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  15. Mingshan Xue

    Department of Neuroscience, Baylor College of Medicine, Houston, United States
    For correspondence
    mxue@bcm.edu
    Competing interests
    Mingshan Xue, MX is a consultant to Capsida Biotherapeutics and receives funds from Capsida Biotherapeutics for research not related to this study..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1463-8884

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.

Reviewing Editor

  1. Samuel Pleasure, University of California, San Francisco, United States

Publication history

  1. Preprint posted: June 19, 2022 (view preprint)
  2. Received: July 15, 2022
  3. Accepted: December 30, 2022
  4. Accepted Manuscript published: January 3, 2023 (version 1)

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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  1. Dongwon Lee
  2. Wu Chen
  3. Heet Naresh Kaku
  4. Xinming Zhuo
  5. Eugene S Chao
  6. Armand Soriano
  7. Allen Kuncheria
  8. Stephanie Flores
  9. Joo Hyun Kim
  10. Armando Rivera
  11. Frank Rigo
  12. Paymaan Jafar-nejad
  13. Arthur L Beaudet
  14. Matthew S Caudill
  15. Mingshan Xue
(2023)
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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