Antisense oligonucleotide therapy rescues disturbed brain rhythms and sleep in juvenile and adult mouse models of Angelman syndrome
Curation statements for this article:-
Curated by eLife
eLife assessment
This manuscript has a number of important findings in the interesting area of attempts to rescue neurodevelopmental phenotypes in the postnatal setting. Ameliorating some of the symptoms of Angelman syndrome at later stages is potentially of major clinical significance and this study provides support for that possibility. More generally, this study also shows that treatment of a syndrome like Angelman with antisense oligonucleotides to modulate allele-specific expression at later stages of life has potential.
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (eLife)
- Neuroscience (eLife)
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.
Article activity feed
-
-
eLife assessment
This manuscript has a number of important findings in the interesting area of attempts to rescue neurodevelopmental phenotypes in the postnatal setting. Ameliorating some of the symptoms of Angelman syndrome at later stages is potentially of major clinical significance and this study provides support for that possibility. More generally, this study also shows that treatment of a syndrome like Angelman with antisense oligonucleotides to modulate allele-specific expression at later stages of life has potential.
-
Reviewer #1 (Public Review):
This is an important and timely manuscript describing the use of anti-sense oligos (ASO) to re-activate the silent paternal allele of Ube3a in juvenile and adult Ube3a deficient mice. The main finding presented here is that rescue at these postnatal stages appears to rescue EEG power and sleep problems, if not balance/ataxia and anxiety.
Previous studies have shown that through genetic manipulation, Ube3a can be turned on developmentally in a Ube3a deficient background at embryonic stages with complete rescue of "critical" phenotypes (ataxia, anxiety, repetitive behavior and epilepsy). The current study suggests that at least EEG power and sleep rhythms can be rescued at the juvenile and, to a lesser extent, adult stages. However, these previous studies did not examine EEG or sleep disturbance in any detail …
Reviewer #1 (Public Review):
This is an important and timely manuscript describing the use of anti-sense oligos (ASO) to re-activate the silent paternal allele of Ube3a in juvenile and adult Ube3a deficient mice. The main finding presented here is that rescue at these postnatal stages appears to rescue EEG power and sleep problems, if not balance/ataxia and anxiety.
Previous studies have shown that through genetic manipulation, Ube3a can be turned on developmentally in a Ube3a deficient background at embryonic stages with complete rescue of "critical" phenotypes (ataxia, anxiety, repetitive behavior and epilepsy). The current study suggests that at least EEG power and sleep rhythms can be rescued at the juvenile and, to a lesser extent, adult stages. However, these previous studies did not examine EEG or sleep disturbance in any detail and may have missed these clinically relevant phenotypes.
Clearly, the current manuscript addresses the issue of rescue postnatally, which is more likely in a clinical setting as Angelman therapeutics are developed. The impact of the EEG rescue is yet to be determined, as the authors did not do these studies in a 129sv background, it is impossible to tell if they could rescue the seizure phenotype in Ube3a deficient mice (c57BL/6 mice are resistant to seizure). The finding that the ASOs could rescue defects in REM sleep may be the most important results in the current study as it stands. Children with AS suffer from sleep problems, as do their caregivers, since REM sleep is disrupted, and they have difficulty sleeping through the night. In sum, I think the authors make a strong case that at least some clinically relevant phenotypes can be rescued using ASO approaches postnatally in Ube3a deficient mice. The need for more information on which isoforms of Ube3a are rescued and whether cognitive defects are rescued as well by late ASO therapeutics is a critical weakness of the current study as it stands. -
Reviewer #2 (Public Review):
Lee, Chen, Kaku, Zhuo et. al. demonstrate that a single injection of ube3a-ASO in a new mutant ube3a mouse model restores Ube3a protein expression and EEG function and sleep patterns. A key feature of these findings is the development of a new mouse model that eliminates any expression of ube3a mRNA. Moreover, they demonstrate that the impact of their treatment can last up to 6 weeks. They determine that the phenotype correction correlates with Ube3a protein level. There is an impressive amount of work that has gone into this study. It does appear, however, that much of this work is derivative of previous studies. It is less clear what is novel. While a new mouse model is introduced, it is unclear whether such a mouse model is any better defining Angelman syndrome than previous models. Several conclusions …
Reviewer #2 (Public Review):
Lee, Chen, Kaku, Zhuo et. al. demonstrate that a single injection of ube3a-ASO in a new mutant ube3a mouse model restores Ube3a protein expression and EEG function and sleep patterns. A key feature of these findings is the development of a new mouse model that eliminates any expression of ube3a mRNA. Moreover, they demonstrate that the impact of their treatment can last up to 6 weeks. They determine that the phenotype correction correlates with Ube3a protein level. There is an impressive amount of work that has gone into this study. It does appear, however, that much of this work is derivative of previous studies. It is less clear what is novel. While a new mouse model is introduced, it is unclear whether such a mouse model is any better defining Angelman syndrome than previous models. Several conclusions appear to be a bit too strong based on the modesty of the findings. For example, it is not clear that the current findings constitute a strong enough foundation for future drug studies.
Overall, this study describes another set of potentially interesting findings using ASO to restore Ube3a expression and phenotypic rescue. Not all phenotypes are tested, not every tested phenotype shows truly robust changes that would encourage one to move to clinical trials.
The authors did succeed in describing this new mouse line at the level of ube3a expression, EEG, sleep patterns and poly-spikes. They did so across many brain regions and multiple ages. Within these findings and approaches, there is useful information that can benefit the field. The impact of this work is that the authors may have demonstrated an approach which will have a longer lasting impact on recovery. Such an advance would be a great benefit to the population of those greatly impacted by Angelman syndrome.
-
Reviewer #3 (Public Review):
Normal levels of UBE3A expression in neurons are from the maternal allele whereas its paternal allele is repressed by its antisense transcript (UBE3A-ATS). In Angelman syndrome, a severe neurodevelopmental disorder, the combined lack of maternal UBE3A expression and paternal repression led to UBE3A deficiency. The oligonucleotide therapeutic approach holds a promise to treat Angelman syndrome by suppressing UBE3A-ATS and reactivating the paternal UBE3A allele. Previous studies showed the effectiveness of this method in early development. This narrow and rather restricted therapeutic window limits its potential in treatment. This research aims to test the idea that it is possible to expand the therapeutic window. They first developed a new maternal Ube3a knockout mouse model of Angelman syndrome and then use …
Reviewer #3 (Public Review):
Normal levels of UBE3A expression in neurons are from the maternal allele whereas its paternal allele is repressed by its antisense transcript (UBE3A-ATS). In Angelman syndrome, a severe neurodevelopmental disorder, the combined lack of maternal UBE3A expression and paternal repression led to UBE3A deficiency. The oligonucleotide therapeutic approach holds a promise to treat Angelman syndrome by suppressing UBE3A-ATS and reactivating the paternal UBE3A allele. Previous studies showed the effectiveness of this method in early development. This narrow and rather restricted therapeutic window limits its potential in treatment. This research aims to test the idea that it is possible to expand the therapeutic window. They first developed a new maternal Ube3a knockout mouse model of Angelman syndrome and then use antisense oligonucleotides to repress Ube3a-ATS targeting both juvenile and adult mice. This approach increased UBE3A expression from the paternal locus and to a large degree rescued the abnormal EEG rhythm and sleep quality, two core clinical symptoms of patients. Overall, this is a well-designed and executed study. The authors did a thorough analysis of UBE3A expression levels in different brain regions under different conditions which correlated well with functional data. Further, the manuscript is also well written. This reviewer had several concerns, including Western blot data presentation, ICV injection validation, and possible improvement in cognitive functions. The reviewer believes that the authors should be able to address these issues readily.
-
-