Angelman Syndrome: How late is too late for treatment?

Experiments on mice suggest that an approach called antisense oligonucleotide therapy may be able to treat some symptoms of Angelman syndrome, including problems with epilepsy and sleep.
  1. Lawrence T Reiter  Is a corresponding author
  1. Department of Neurology, Department of Pediatrics, Department of Anatomy and Neurobiology, College of Medicine, University of Tennessee Health Science Center, United States

An approach called antisense oligonucleotide (ASO) therapy has ushered in a new age in genetic medicine. ASO therapy works by introducing a short strand of RNA that binds to specific messenger RNA (mRNA) molecules in the host, and thus prevents the mRNA from being translated. Clinical trials are currently under way to see if ASO therapy will work for various neurodevelopmental disorders, including Dravet syndrome (an epilepsy disorder), spinal muscular atrophy (a neuromuscular condition) and Batten’s disease (a devastating lysosomal storage disorder; Hill and Meisler, 2021).

Angelman syndrome is a neurodevelopmental disorder that is considered an ideal candidate for ASO therapy. Symptoms appear very early in childhood and include learning disabilities, abnormally happy demeanor, epilepsy, and difficulty controlling motor function, particularly while walking (Dagli et al., 1993). Children with Angelman syndrome also suffer from sleep problems. It has previously been shown, using cellular and animal models, that the regulation of a single gene, UBE3A, in the nervous system leads to the major features of Angelman syndrome (Kishino et al., 1997; Matsuura et al., 1997; Sutcliffe et al., 1997). UBE3A is found on chromosome 15, and most cases of Angelman syndrome are the result of a large deletion in the maternal copy of this chromosome. This means that most individuals have a working – but silent – paternal copy of UBE3A on chromosome 15. However, this copy is silenced by an antisense transcript which interferes with the expression of the paternal UBE3A.

Using ASO therapy to interfere with the antisense transcript – and thus allowing the intact copy of UBE3A to be expressed – is a promising approach for the treatment of Angelman syndrome. However, some scientists remain skeptical about the potential for ASO therapy to treat neurodevelopmental disorders, and several questions remain regarding how these treatments will work. For example, when does it become too late in human development to reactivate a missing gene in the nervous system? Are there neurogenetic diseases that can be rescued in adulthood? And, if so, what features of the disease can be treated with ASO therapies?

Extensive research has focused on answering these questions by reactivating the paternal copy UBE3A in a commonly used mouse model for Angelman syndrome. One goal of these studies has been to determine which symptoms can be reduced or eliminated. Another goal, which may be more challenging to achieve, is to establish when the gene should be reactivated during development in order to achieve the desired effect.

In 2018, researchers at the Erasmus Medical Center in Rotterdam published a set of behaviors that can be used to assess phenotypes for motor performance, repetitive behavior, anxiety, and seizure susceptibility using Ube3a maternal deficient mice (Sonzogni et al., 2018). These behaviors provide a framework to test the effectiveness of drugs (or ASOs) that reactivate the silent paternal copy of the gene. However, there are not many studies that dig deeper into the cognitive issues, sleep or epilepsy-related brain activity (as measured with EEG) that are known to be affected in this mouse model. Now, in eLife, Mingshan Xue and colleagues from Baylor College of Medicine and Ionis Pharmaceuticals – including Dongwon Lee, Wu Chen, Heet Naresh Kaku and Xinming Zhuo as first authors – report on the use of an ASO to rescue the characteristic EEG pattern and disordered sleep observed in a mouse model of Angelman syndrome (Lee et al., 2023).

First, Lee et al. designed a new Angelman syndrome mouse model that is less ‘leaky’ than the model used by other labs in previous studies – that is, a model where Ube3a expression from the maternal chromosome was more completely blocked. Then they injected the mice with an ASO against the Ube3a antisense transcript to see if the expression of the Ube3a protein could be rescued from the paternal chromosome. The results showed that, after injecting the mice with the ASO, the levels of Ube3a protein increased in multiple regions of the brain, including the cortex, the hippocampus and the hypothalamus, which controls sleep. Importantly, Ube3a expression was rescued in both juvenile and adult animals, which had previously been challenging.

Next, Lee et al. showed that the electrical activity in the brain of these mice is significantly rescued by injection of this ASO, in both juvenile and adult animals. They were also able to rescue the low level of rapid eye movement (REM) sleep observed in individuals with Angelman syndrome, with animals getting an almost normal amount of REM sleep six weeks after injection with the ASO.

The findings of Lee et al. illustrate that it may be possible to treat some aspects of Angelman syndrome after birth, and even into adulthood, using ASO therapeutics. This challenges the current view of what symptoms of Angelman syndrome are treatable, and at what age. While the delivery of ASOs to the brain is still a struggle, the latest results are encouraging for potential treatments for Angelman syndrome, and perhaps other neurodevelopmental disorders thought to be untreatable after birth.

References

  1. Website
    1. Dagli AI
    2. Mathews J
    3. Williams CA
    (1993) Angelman syndrome
    GeneReviews. Accessed February 2, 2023.

Article and author information

Author details

  1. Lawrence T Reiter

    Lawrence T Reiter is in the Department of Neurology, the Department of Pediatrics and the Department of Anatomy and Neurobiology, College of Medicine, University of Tennessee Health Science Center, Memphis, United States

    For correspondence
    lreiter@uthsc.edu
    Competing interests
    No competing interests declared
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4100-2630

Publication history

  1. Version of Record published: February 7, 2023 (version 1)

Copyright

© 2023, Reiter

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,173
    Page views
  • 42
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Lawrence T Reiter
(2023)
Angelman Syndrome: How late is too late for treatment?
eLife 12:e86117.
https://doi.org/10.7554/eLife.86117

Further reading

    1. Medicine
    Xiaoyan Yang, Hsiang-Chun Chang ... Hossein Ardehali
    Research Article

    Sirtuins (SIRT) exhibit deacetylation or ADP-ribosyltransferase activity and regulate a wide range of cellular processes in the nucleus, mitochondria and cytoplasm. The role of the only sirtuin that resides in the cytoplasm, SIRT2, in the development of ischemic injury and cardiac hypertrophy is not known. In this paper, we show that the hearts of mice with deletion of Sirt2 (Sirt2-/-) display improved cardiac function after ischemia-reperfusion (I/R) and pressure overload (PO), suggesting that SIRT2 exerts maladaptive effects in the heart in response to stress. Similar results were obtained in mice with cardiomyocyte-specific Sirt2 deletion. Mechanistic studies suggest that SIRT2 modulates cellular levels and activity of nuclear factor (erythroid-derived 2)-like 2 (NRF2), which results in reduced expression of antioxidant proteins. Deletion of Nrf2 in the hearts of Sirt2-/- mice reversed protection after PO. Finally, treatment of mouse hearts with a specific SIRT2 inhibitor reduced cardiac size and attenuates cardiac hypertrophy in response to PO. These data indicate that SIRT2 has detrimental effects in the heart and plays a role in cardiac response to injury and the progression of cardiac hypertrophy, which makes this protein a unique member of the SIRT family. Additionally, our studies provide a novel approach for treatment of cardiac hypertrophy and injury by targeting SIRT2 pharmacologically, providing a novel avenue for the treatment of these disorders.

    1. Medicine
    Luyang Cao, Lixiang Ma ... Jingsong Xu
    Research Article

    Billions of apoptotic cells are removed daily in a human adult by professional phagocytes (e.g. macrophages) and neighboring nonprofessional phagocytes (e.g. stromal cells). Despite being a type of professional phagocyte, neutrophils are thought to be excluded from apoptotic sites to avoid tissue inflammation. Here, we report a fundamental and unexpected role of neutrophils as the predominant phagocyte responsible for the clearance of apoptotic hepatic cells in the steady state. In contrast to the engulfment of dead cells by macrophages, neutrophils burrowed directly into apoptotic hepatocytes, a process we term perforocytosis, and ingested the effete cells from the inside. The depletion of neutrophils caused defective removal of apoptotic bodies, induced tissue injury in the mouse liver, and led to the generation of autoantibodies. Human autoimmune liver disease showed similar defects in the neutrophil-mediated clearance of apoptotic hepatic cells. Hence, neutrophils possess a specialized immunologically silent mechanism for the clearance of apoptotic hepatocytes through perforocytosis, and defects in this key housekeeping function of neutrophils contribute to the genesis of autoimmune liver disease.