Emerging Gene and Small Molecule Therapies for the Neurodevelopmental Disorder Angelman Syndrome

AbstractAngelman syndrome (AS) is a rare (~1:15,000) neurodevelopmental disorder characterized by severe developmental delay and intellectual disability, impaired communication skills, and a high prevalence of seizures, sleep disturbances, ataxia, motor deficits, and microcephaly. AS is caused by loss-of-function of the maternally inherited UBE3A gene. UBE3A is located on chromosome 15q11–13 and is biallelically expressed throughout the body but only maternally expressed in the brain due to an RNA antisense transcript that silences the paternal copy. There is currently no cure for AS, but advancements in small molecule drugs and gene therapies offer a promising approach for the treatment of the disorder. Here, we review AS and how loss-of-function of the maternal UBE3A contributes to the disorder. We also discuss the strengths and limitations of current animal models of AS. Furthermore, we examine potential small molecule drug and gene therapies for the treatment of AS and associated challenges faced by the therapeutic design. Finally, gene therapy offers the opportunity for precision medicine in AS and advancements in the treatment of this disorder can serve as a foundation for other single-gene neurodevelopmental disorders.

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Seizure-like activity in a juvenile Angelman syndrome mouse model is attenuated by reducing Arc expression

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1504809112 ◽

2015 ◽

Vol 112 (16) ◽

pp. 5129-5134 ◽

Cited By ~ 45

Author(s):

Caleigh Mandel-Brehm ◽

John Salogiannis ◽

Sameer C. Dhamne ◽

Alexander Rotenberg ◽

Michael E. Greenberg

Keyword(s):

Angelman Syndrome ◽

Motor Coordination ◽

Neural Circuit ◽

Brain Activity ◽

Neurodevelopmental Disorder ◽

Ultrasonic Vocalizations ◽

Therapeutic Interventions ◽

Motor Deficits ◽

Loss Of Function ◽

Circuit Defects

Angelman syndrome (AS) is a neurodevelopmental disorder arising from loss-of-function mutations in the maternally inherited copy of the UBE3A gene, and is characterized by an absence of speech, excessive laughter, cognitive delay, motor deficits, and seizures. Despite the fact that the symptoms of AS occur in early childhood, behavioral characterization of AS mouse models has focused primarily on adult phenotypes. In this report we describe juvenile behaviors in AS mice that are strain-independent and clinically relevant. We find that young AS mice, compared with their wild-type littermates, produce an increased number of ultrasonic vocalizations. In addition, young AS mice have defects in motor coordination, as well as abnormal brain activity that results in an enhanced seizure-like response to an audiogenic challenge. The enhanced seizure-like activity, but not the increased ultrasonic vocalizations or motor deficits, is rescued in juvenile AS mice by genetically reducing the expression level of the activity-regulated cytoskeleton-associated protein, Arc. These findings suggest that therapeutic interventions that reduce the level of Arc expression have the potential to reverse the seizures associated with AS. In addition, the identification of aberrant behaviors in young AS mice may provide clues regarding the neural circuit defects that occur in AS and ultimately allow new approaches for treating this disorder.

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O’Donnell-Luria-Rodan syndrome: description of a second multinational cohort and refinement of the phenotypic spectrum

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-107470 ◽

2021 ◽

pp. jmedgenet-2020-107470

Author(s):

Clara Velmans ◽

Anne H O'Donnell-Luria ◽

Emanuela Argilli ◽

Frederic Tran Mau-them ◽

Antonio Vitobello ◽

...

Keyword(s):

Sleep Disturbances ◽

Single Gene ◽

Neurodevelopmental Disorder ◽

Case Series ◽

Autism Spectrum ◽

Mild Intellectual Disability ◽

Neurodevelopmental Delay ◽

Phenotypic Spectrum ◽

High Prevalence ◽

High Relative Frequency

BackgroundO’Donnell-Luria-Rodan syndrome (ODLURO) is an autosomal-dominant neurodevelopmental disorder caused by pathogenic, mostly truncating variants in KMT2E. It was first described by O’Donnell-Luria et al in 2019 in a cohort of 38 patients. Clinical features encompass macrocephaly, mild intellectual disability (ID), autism spectrum disorder (ASD) susceptibility and seizure susceptibility.MethodsAffected individuals were ascertained at paediatric and genetic centres in various countries by diagnostic chromosome microarray or exome/genome sequencing. Patients were collected into a case cohort and were systematically phenotyped where possible.ResultsWe report 18 additional patients from 17 families with genetically confirmed ODLURO. We identified 15 different heterozygous likely pathogenic or pathogenic sequence variants (14 novel) and two partial microdeletions of KMT2E. We confirm and refine the phenotypic spectrum of the KMT2E-related neurodevelopmental disorder, especially concerning cognitive development, with rather mild ID and macrocephaly with subtle facial features in most patients. We observe a high prevalence of ASD in our cohort (41%), while seizures are present in only two patients. We extend the phenotypic spectrum by sleep disturbances.ConclusionOur study, bringing the total of known patients with ODLURO to more than 60 within 2 years of the first publication, suggests an unexpectedly high relative frequency of this syndrome worldwide. It seems likely that ODLURO, although just recently described, is among the more common single-gene aetiologies of neurodevelopmental delay and ASD. We present the second systematic case series of patients with ODLURO, further refining the mutational and phenotypic spectrum of this not-so-rare syndrome.

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BIOLOGICAL SCIENCES: Genetics

10.1101/404061 ◽

2018 ◽

Author(s):

Jack S. Hsiao ◽

Noelle D. Germain ◽

Andrea Wilderman ◽

Christopher Stoddard ◽

Luke A. Wojenski ◽

...

Keyword(s):

Boundary Element ◽

Angelman Syndrome ◽

Antisense Transcript ◽

Neurodevelopmental Disorder ◽

Boundary Function ◽

Paternal Allele ◽

Loss Of Function ◽

Maternal Allele ◽

Specific Expression ◽

Human Neurons

ABSTRACTAngelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function from the maternal allele of UBE3A, a gene encoding an E3 ubiquitin ligase. UBE3A is only expressed from the maternally-inherited allele in mature human neurons due to tissue-specific genomic imprinting. Imprinted expression of UBE3A is restricted to neurons by expression of UBE3A antisense transcript (UBE3A-ATS) from the paternally-inherited allele, which silences the paternal allele of UBE3A in cis. However, the mechanism restricting UBE3A-ATS expression and UBE3A imprinting to neurons is not understood. We used CRISPR/Cas9-mediated genome editing to functionally define a bipartite boundary element critical for neuron-specific expression of UBE3A-ATS in humans. Removal of this element led to upregulation of UBE3A-ATS without repressing paternal UBE3A. However, increasing expression of UBE3A-ATS in the absence of the boundary element resulted in full repression of paternal UBE3A, demonstrating that UBE3A imprinting requires both the loss of function from the boundary element as well as upregulation of UBE3A-ATS. These results suggest that manipulation of the competition between UBE3A-ATS and UBE3A may provide a potential therapeutic approach for AS.SIGNIFICANCE STATEMENTAngelman syndrome is a neurodevelopmental disorder caused by loss of function from the maternal allele of UBE3A, an imprinted gene. The paternal allele of UBE3A is silenced by a long, non-coding antisense transcript in mature neurons. We have identified a boundary element that stops the transcription of the antisense transcript in human pluripotent stem cells, and thus restricts UBE3A imprinted expression to neurons. We further determined that UBE3A imprinting requires both the loss of the boundary function and sufficient expression of the antisense transcript to silence paternal UBE3A. These findings provide essential details about the mechanisms of UBE3A imprinting that may suggest additional therapeutic approaches for Angelman syndrome.

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Identification of disease-linked hyperactivating mutations in UBE3A through large-scale functional variant analysis

Nature Communications ◽

10.1038/s41467-021-27156-0 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Kellan P. Weston ◽

Xiaoyi Gao ◽

Jinghan Zhao ◽

Kwang-Soo Kim ◽

Susan E. Maloney ◽

...

Keyword(s):

Angelman Syndrome ◽

Large Scale ◽

Phenotypic Diversity ◽

Function Analysis ◽

Genetic Disorders ◽

Neurodevelopmental Disorder ◽

Loss Of Function ◽

Monogenic Disorders ◽

Functional Variant ◽

Variant Analysis

AbstractThe mechanisms that underlie the extensive phenotypic diversity in genetic disorders are poorly understood. Here, we develop a large-scale assay to characterize the functional valence (gain or loss-of-function) of missense variants identified in UBE3A, the gene whose loss-of-function causes the neurodevelopmental disorder Angelman syndrome. We identify numerous gain-of-function variants including a hyperactivating Q588E mutation that strikingly increases UBE3A activity above wild-type UBE3A levels. Mice carrying the Q588E mutation exhibit aberrant early-life motor and communication deficits, and individuals possessing hyperactivating UBE3A variants exhibit affected phenotypes that are distinguishable from Angelman syndrome. Additional structure-function analysis reveals that Q588 forms a regulatory site in UBE3A that is conserved among HECT domain ubiquitin ligases and perturbed in various neurodevelopmental disorders. Together, our study indicates that excessive UBE3A activity increases the risk for neurodevelopmental pathology and suggests that functional variant analysis can help delineate mechanistic subtypes in monogenic disorders.

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Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice

Scientific Reports ◽

10.1038/s41598-021-97898-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Gabrielle L. Sell ◽

Wendy Xin ◽

Emily K. Cook ◽

Mark A. Zbinden ◽

Thomas B. Schaffer ◽

...

Keyword(s):

Angelman Syndrome ◽

Developmental Disorders ◽

Motor Coordination ◽

Synapse Formation ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Loss Of Function ◽

Behavioral Deficits ◽

Altered Expression ◽

Exciting Potential

AbstractIn humans, loss-of-function mutations in the UBE3A gene lead to the neurodevelopmental disorder Angelman syndrome (AS). AS patients have severe impairments in speech, learning and memory, and motor coordination, for which there is currently no treatment. In addition, UBE3A is duplicated in > 1–2% of patients with autism spectrum disorders—a further indication of the significant role it plays in brain development. Altered expression of UBE3A, an E3 ubiquitin ligase, is hypothesized to lead to impaired levels of its target proteins, but identifying the contribution of individual UBE3A targets to UBE3A-dependent deficits remains of critical importance. Ephexin5 is a putative UBE3A substrate that has restricted expression early in development, regulates synapse formation during hippocampal development, and is abnormally elevated in AS mice, modeled by maternally-derived Ube3a gene deletion. Here, we report that Ephexin5 can be directly ubiquitylated by UBE3A. Furthermore, removing Ephexin5 from AS mice specifically rescued hippocampus-dependent behaviors, CA1 physiology, and deficits in dendritic spine number. Our findings identify Ephexin5 as a key driver of hippocampal dysfunction and related behavioral deficits in AS mouse models. These results demonstrate the exciting potential of targeting Ephexin5, and possibly other UBE3A substrates, to improve symptoms of AS and other UBE3A-related developmental disorders.

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Deleting a UBE3A substrate rescues impaired hippocampal physiology and learning in Angelman syndrome mice

10.1101/625418 ◽

2019 ◽

Author(s):

Gabrielle L. Sell ◽

Wendy Xin ◽

Emily K. Cook ◽

Mark A. Zbinden ◽

Thomas B. Schaffer ◽

...

Keyword(s):

Ubiquitin Ligase ◽

Angelman Syndrome ◽

Developmental Disorders ◽

Motor Coordination ◽

Synapse Formation ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Loss Of Function ◽

Altered Expression ◽

Exciting Potential

ABSTRACTIn humans, loss-of-function mutations in the UBE3A gene lead to the neurodevelopmental disorder Angelman syndrome (AS). AS patients have severe impairments in speech, learning and memory, and motor coordination, for which there is currently no treatment. In addition, UBE3A is duplicated in >1-2% of patients with autism spectrum disorders – a further indication of the significant role it plays in brain development. Altered expression of UBE3A, an E3 ubiquitin ligase, is hypothesized to lead to impaired levels of its target proteins, but identifying the contribution of individual UBE3A targets to UBE3A-dependent deficits remains of critical importance. Ephexin5 is a putative UBE3A substrate that has restricted expression early in development, regulates synapse formation during hippocampal development, and is abnormally elevated in AS mice, modeled by maternally-derived Ube3a gene deletion. Here, we report that Ephexin5 is a direct substrate of UBE3A ubiquitin ligase activity. Furthermore, removing Ephexin5 from AS mice specifically rescued hippocampus-dependent behaviors, CA1 physiology, and deficits in dendritic spine number. Our findings identify Ephexin5 as a key driver of hippocampal dysfunction and related behavioral deficits in AS mouse models. These results demonstrate the exciting potential of targeting Ephexin5, and possibly other UBE3A substrates, to improve symptoms of AS and other UBE3A-related developmental disorders.

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Red blood cells in Rett syndrome: oxidative stress, morphological changes and altered membrane organization

Biological Chemistry ◽

10.1515/hsz-2015-0117 ◽

2015 ◽

Vol 396 (11) ◽

pp. 1233-1240 ◽

Cited By ~ 10

Author(s):

Lucia Ciccoli ◽

Claudio De Felice ◽

Silvia Leoncini ◽

Cinzia Signorini ◽

Alessio Cortelazzo ◽

...

Keyword(s):

Rett Syndrome ◽

Morphological Changes ◽

Single Gene ◽

Neurodevelopmental Disorder ◽

Gene Mutations ◽

Autism Spectrum ◽

Current Evidence ◽

Loss Of Function ◽

Beneficial Effects ◽

Spectrum Disorders

Abstract In this review, we summarize the current evidence on the erythrocyte as a previously unrecognized target cell in Rett syndrome, a rare (1:10 000 females) and devastating neurodevelopmental disorder caused by loss-of-function mutations in a single gene (i.e. MeCP2, CDKL5, or rarely FOXG1). In particular, we focus on morphological changes, membrane oxidative damage, altered membrane fatty acid profile, and aberrant skeletal organization in erythrocytes from patients with typical Rett syndrome and MeCP2 gene mutations. The beneficial effects of ω-3 polyunsaturated fatty acids (PUFAs) are also summarized for this condition to be considered as a ‘model’ condition for autism spectrum disorders.

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Gene Therapy for Angelman Syndrome: Contemporary Approaches and Future Endeavors

Current Gene Therapy ◽

10.2174/1566523220666200107151025 ◽

2020 ◽

Vol 19 (6) ◽

pp. 359-366 ◽

Cited By ~ 2

Author(s):

Christos Tsagkaris ◽

Vasiliki Papakosta ◽

Adriana Viola Miranda ◽

Lefkothea Zacharopoulou ◽

Valeriia Danilchenko ◽

...

Keyword(s):

Gene Therapy ◽

Signaling Pathways ◽

Angelman Syndrome ◽

Topoisomerase I ◽

Neurodevelopmental Disorder ◽

Multiple Roles ◽

Therapeutic Effects ◽

Gene Therapies ◽

Keywords Gene Therapy ◽

Cell Signaling Pathways

Background: Angelman Syndrome (AS) is a congenital non inherited neurodevelopmental disorder. The contemporary AS management is symptomatic and it has been accepted that gene therapy may play a key role in the treatment of AS. Objective: The purpose of this study is to summarize existing and suggested gene therapy approaches to Angelman syndrome. Methods: This is a literature review. Pubmed and Scopus databases were researched with keywords (gene therapy, Angelman’s syndrome, neurological disorders, neonates). Peer-reviewed studies that were closely related to gene therapies in Angelman syndrome and available in English, Greek, Ukrainian or Indonesian were included. Studies that were published before 2000 were excluded and did not align with the aforementioned criteria. Results: UBE3A serves multiple roles in signaling and degradation procedures. Although the restoration of UBE3A expression rather than targeting known activities of the molecule would be the optimal therapeutic goal, it is not possible so far. Reinstatement of paternal UBE3A appears as an adequate alternative. This can be achieved by administering topoisomerase-I inhibitors or reducing UBE3A antisense transcript (UBE3A-ATS), a molecule which silences paternal UBE3A. Conclusion: Understanding UBE3A imprinting unravels the path to an etiologic treatment of AS. Gene therapy models tested on mice appeared less effective than anticipated pointing out that activation of paternal UBE3A cannot counteract the existing CNS defects. On the other hand, targeting abnormal downstream cell signaling pathways has provided promising rescue effects. Perhaps, combined reinstatement of paternal UBE3A expression with abnormal signaling pathways-oriented treatment is expected to provide better therapeutic effects. However, AS gene therapy remains debatable in pharmacoeconomics and ethics context.

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Understanding the Pathogenesis of Angelman Syndrome through Animal Models

Neural Plasticity ◽

10.1155/2012/710943 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 27

Author(s):

Nihar Ranjan Jana

Keyword(s):

Animal Models ◽

Angelman Syndrome ◽

Neurodevelopmental Disorder ◽

Synaptic Function ◽

Loss Of Function ◽

Disease Biology ◽

Regulation Of Activity ◽

Fundamental Insight ◽

Motor Abnormalities ◽

Activity Dependent

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe mental retardation, lack of speech, ataxia, susceptibility to seizures, and unique behavioral features such as easily provoked smiling and laughter and autistic features. The disease is primarily caused by deletion or loss-of-function mutations of the maternally inheritedUBE3Agene located within chromosome 15q11-q13. TheUBE3Agene encodes a 100 kDa protein that functions as ubiquitin ligase and transcriptional coactivator. Emerging evidence now indicates that UBE3A plays a very important role in synaptic function and in regulation of activity-dependent synaptic plasticity. A number of animal models for AS have been generated to understand the disease pathogenesis. The most widely used model is theUBE3A-maternal-deficient mouse that recapitulates most of the essential features of AS including cognitive and motor abnormalities. This paper mainly discusses various animal models of AS and how these models provide fundamental insight into understanding the disease biology for potential therapeutic intervention.

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Schistosomal Appendicitis in Pregnancy

Swiss Surgery ◽

10.1024/1023-9332.8.3.121 ◽

2002 ◽

Vol 8 (3) ◽

pp. 121-122 ◽

Cited By ~ 9

Author(s):

Halkic ◽

Abdelmoumene ◽

Gintzburger ◽

Mosimann

Keyword(s):

Acute Appendicitis ◽

Schistosoma Haematobium ◽

Acute Inflammation ◽

The Body ◽

Parasitic Infections ◽

Common Complication ◽

Surgical Infection ◽

High Prevalence ◽

Potential Challenge ◽

In Pregnancy

Acute appendicitis is the most common acute surgical infection during pregnancy. Although usually pyogenic in origin, parasitic infections account for a small percentage of cases. Despite the relatively high prevalence of acute appendicitis in our environment, it is not commonly associated with schistosomiasis. We report here the association of pregnancy and appendicitis caused by Schistosoma haematobium. Schistosomiasis is very common complication of pregnancy in hyperendemic areas. Schistosome egg masses can lodge throughout the body and cause acute inflammation of the appendix, liver and spleen. Congestion of pelvic vessels during pregnancy facilitates passage of eggs into the villi and intervillous spaces, causing an inflammatory reaction. Tourism and immigration make this disease a potential challenge for practitioners everywhere.

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