Dual-isoform hUBE3A gene transfer improves behavioral and seizure outcomes in Angelman syndrome model mice

Judson, Matthew C.; Shyng, Charles; Simon, Jeremy M.; Davis, Courtney R.; Punt, A. Mattijs; Salmon, Mirabel T.; Miller, Noah W.; Ritola, Kimberly; Elgersma, Ype; Amaral, David G.; Gray, Steven J.; Philpot, Benjamin D.

doi:10.1172/jci.insight.144712

Cited by 23 publications

(17 citation statements)

References 88 publications

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“…Developing a pipeline to test new AS treatments in mice will be critical to evaluate their success, regardless of treatment mechanism. Recent work established a “gold standard” behavioral battery consisting of five tests (rotarod, open field, marble burying, nest building, forced swim) that are reliably impaired in Ube3a m-/p+ mice [ 24 ] and are sensitive to treatment [ 40 , 44 – 46 ]. Using this battery, we hypothesized that multidimensional analysis: (a) would enable quantification of behavior across multiple domains as a single “severity score,” (b) that this severity score would be a reliable indicator of Ube3a genotype, and (c) that this severity score is sensitive to treatment.…”

Section: Introductionmentioning

confidence: 99%

Multidimensional analysis of behavior predicts genotype with high accuracy in a mouse model of Angelman syndrome

Tanas¹,

Kerr

Wang³

et al. 2022

Transl Psychiatry

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Angelman syndrome (AS) is a neurodevelopmental disorder caused by loss of expression of the maternal copy of the UBE3A gene. Individuals with AS have a multifaceted behavioral phenotype consisting of deficits in motor function, epilepsy, cognitive impairment, sleep abnormalities, as well as other comorbidities. Effectively modeling this behavioral profile and measuring behavioral improvement will be crucial for the success of ongoing and future clinical trials. Foundational studies have defined an array of behavioral phenotypes in the AS mouse model. However, no single behavioral test is able to fully capture the complex nature of AS—in mice, or in children. We performed multidimensional analysis (principal component analysis + k-means clustering) to quantify the performance of AS model mice (n = 148) and wild-type littermates (n = 138) across eight behavioral domains. This approach correctly predicted the genotype of mice based on their behavioral profile with ~95% accuracy, and remained effective with reasonable sample sizes (n = ~12–15). Multidimensional analysis was effective using different combinations of behavioral inputs and was able to detect behavioral improvement as a function of treatment in AS model mice. Overall, multidimensional behavioral analysis provides a tool for evaluating the effectiveness of preclinical treatments for AS. Multidimensional analysis of behavior may also be applied to rodent models of related neurodevelopmental disorders, and may be particularly valuable for disorders where individual behavioral tests are less reliable than in AS.

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Section: Introductionmentioning

confidence: 99%

Multidimensional analysis of behavior predicts genotype with high accuracy in a mouse model of Angelman syndrome

Tanas¹,

Kerr

Wang³

et al. 2022

Transl Psychiatry

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“…Currently, three Phase 1 or Phase 1/2 clinical trials with ASOs targeting UBE3A-ATS are underway. Another approach is to directly express an exogenous copy of UBE3A by AAV, which also only rescues a subset of phenotypes of maternal Ube3a knockout mice when administered postnatally ( Daily et al, 2011 ; Judson et al, 2021 ). The reversibility of neurological phenotypes at different ages is summarized in Supplementary file 1 .…”

Section: Introductionmentioning

confidence: 99%

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

Lee

Chen

Kaku

et al. 2023

eLife

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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.

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“…While not planned in this case, the group difference in age was beneficial in that it enabled us to study behavior in Ube3a m−/p+ mice in groups that were weight-matched (Supplementary Figure 8B). Increased weight has been widely reported in Ube3a m−/p+ mice (van Woerden et al, 2007;Huang et al, 2013;Born et al, 2017;Judson et al, 2017Judson et al, , 2021Sonzogni et al, 2018;Wolter et al, 2020), and weight differences have the potential to confound behavioral tests. Here, behavioral phenotypes were present on the 5CSRTT in Ube3a m−/p+ mice that were the same weight as WT controls.…”

Section: Discussionmentioning

confidence: 98%

Dissociating motor impairment from five-choice serial reaction time task performance in a mouse model of Angelman syndrome

Negrón-Moreno

Diep

Guoynes

et al. 2022

Front. Behav. Neurosci.

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Angelman syndrome (AS) is a single-gene neurodevelopmental disorder associated with cognitive and motor impairment, seizures, lack of speech, and disrupted sleep. AS is caused by loss-of-function mutations in the UBE3A gene, and approaches to reinstate functional UBE3A are currently in clinical trials in children. Behavioral testing in a mouse model of AS (Ube3am–/p+) represents an important tool to assess the effectiveness of current and future treatments preclinically. Existing behavioral tests effectively model motor impairments, but not cognitive impairments, in Ube3am–/p+ mice. Here we tested the hypothesis that the 5-choice serial reaction time task (5CSRTT) can be used to assess cognitive behaviors in Ube3am–/p+ mice. Ube3am–/p+ mice had more omissions during 5CSRTT training than wild-type littermate controls, but also showed impaired motor function including open field hypoactivity and delays in eating pellet rewards. Motor impairments thus presented an important confound for interpreting this group difference in omissions. We report that despite hypoactivity during habituation, Ube3am–/p+ mice had normal response latencies to retrieve rewards during 5CSRTT training. We also accounted for delays in eating pellet rewards by assessing omissions solely on trials where eating delays would not impact results. Thus, the increase in omissions in Ube3am–/p+ mice is likely not caused by concurrent motor impairments. This work underscores the importance of considering how known motor impairments in Ube3am–/p+ mice may affect behavioral performance in other domains. Our results also provide guidance on how to design a 5CSRTT protocol that is best suited for future studies in Ube3a mutants.

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Dual-isoform hUBE3A gene transfer improves behavioral and seizure outcomes in Angelman syndrome model mice

Cited by 23 publications

References 88 publications

Multidimensional analysis of behavior predicts genotype with high accuracy in a mouse model of Angelman syndrome

Multidimensional analysis of behavior predicts genotype with high accuracy in a mouse model of Angelman syndrome

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

Dissociating motor impairment from five-choice serial reaction time task performance in a mouse model of Angelman syndrome

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