RARE DISEASE
Angelman syndrome
Angelman syndrome
Angelman syndrome
Drug discovery
21
drugs
With orphan designations
Overview
Angelman syndrome is a neurogenetic disorder caused by loss of maternal UBE3A gene function on chromosome 15q11.2-13, leading to severe developmental delay, absent speech, movement/balance disorders (ataxia), seizures, microcephaly, and characteristic happy demeanor. Diagnosis is clinical with genetic confirmation [1][2][4].
Burden
Healthcare utilization: 68% require hospitalization (mean 2.3 admissions), primarily for seizures (40%) and respiratory infections [4][9].
Comorbidities: 80% experience refractory seizures, 72% chronic sleep disturbances, 50% gastrointestinal reflux [4][9][15].
Caregiver impact: Lifelong multidisciplinary care needs contribute to significant emotional/financial strain [5][9].
Therapies
Symptom management: Antiseizure medications (e.g., valproate, CBD trial [3][6]), physical/occupational/speech therapies, sleep training [1][6].
Emerging therapies: Gene-targeting approaches to reactivate paternal UBE3A (antisense oligonucleotides, CRISPR) [8][13][17], with preclinical success in improving seizures and motor function [3][13].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases
Research Papers
394 drug discovery papers about Angelman syndrome, with 5 first-in-class and 12 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
394 drug discovery papers about Angelman syndrome, with 5 first-in-class and 12 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-24 | Parvalbumin interneurons and dentate gyrus homeostatic dysregulation shape epileptogenesis in Angelman syndrome model mice.
Understanding how neural circuits transition from seizure-resistant to seizure-prone is essential for developing improved epilepsy therapies. Here, we study this process by leveraging the heightened susceptibility to seizure kindling of Angelman syndrome (AS) model mice, which lack the maternal Ube3a (mUbe3a) allele. We identify parvalbumin-expressing (PV+) interneurons as critical gatekeepers; selective mUbe3a deletion in PV+ neurons phenocopies enhanced AS epileptogenesis, whereas restoring UBE3A broadly in GABAergic neurons confers seizure resistance. Further, pathological remodeling of the extracellular matrix in the dentate gyrus faithfully tracks with post-kindling seizure susceptibility, highlighting this region's particular relevance to enhanced epileptogenesis. Mechanistically, we uncover a 'two-hit' electrophysiologic phenomenon in AS model mice: kindling fails to recruit compensatory inhibition onto dentate granule cells and instead drives their maladaptive intrinsic hyperexcitability. Together, these findings link cell type-specific inhibitory dysfunction and altered homeostatic plasticity to epileptogenesis, suggesting future circuit-based treatment strategies.
2026-09-22 | Treatment responses to antiseizure medication in children with Angelman syndrome.
Angelman Syndrome (AS) is a rare neurodevelopmental disorder with epilepsy affecting up to 90% of the children. Although several studies have examined antiseizure medications (ASMs) in children with AS, preferred ASMs vary between countries and while new ASMs have become available in clinical practice in recent years, their impact on epilepsy treatment in children with AS remains unclear. We report on the frequency of most prescribed ASMs, responder rates and rate of severe side effects of ASM in a natural history cohort. Epilepsy and epilepsy-related parameters were analyzed including differences between genetic subgroups. A total of 101 children with AS who visited the Angelman center Munich between 2019 and first quarter of 2025 were included in this retrospective analysis. Epilepsy characteristics, frequency of prescribed ASMs, responder rate and severe side effect rate were recorded. Epilepsy was present in 75%, with a higher incidence in the deletion genotype. Most patients experienced seizures rather rarely, but one in five had daily or weekly seizures. Seizure frequency was higher in early childhood. Therapy-refractory epilepsy was observed in 34% of AS children with epilepsy. Rate of therapy-refractory epilepsy and seizure burden was higher in the deletion group. Among the most prescribed ASMs (ethosuximide, levetiracetam and valproate), ethosuximide and valproate demonstrated the highest responder rate (>50% reduction of seizures) in 78% and 75% of patients, respectively, closely followed by levetiracetam (64%). The reported side effect rate of ASM did not differ between the most prescribed medications. The three most prescribed ASMs (valproate, ethosuximide and levetiracetam) in our cohort showed high responder rates in children with Angelman Syndrome. Overall seizure burden and rates of therapy-refractory epilepsy were lower than previously reported, suggesting that combining new and established ASMs may improve seizure outcomes in this population.
2026-09-03 | Aberrant accumulation of α-synuclein might be linked with the progressive motor deficits in a mouse model of Angelman syndrome
Summary Dysfunction of maternal UBE3A leads to Angelman syndrome (AS), which is characterized by significant intellectual and motor debilities. However, the molecular underpinnings of the behavioral deficits associated with UBE3A dysfunction remain obscure. In this study, we utilized a model mouse of AS and report, for the first time, that the aberrant accumulation of α-synuclein may be linked to the development of AS. Firstly, we demonstrated a progressive deterioration of various motor functions in AS mice beginning from the early adolescent phase. Subsequently, we observed an age-dependent increase in the accumulation of both soluble and insoluble α-synuclein, including its pathological variant (pSer129), in the striatum and substantia nigra dopaminergic neurons of AS mice. We also found that Ube3a interacts with α-synuclein and promotes its proteasome-mediated degradation, as evidenced by decreased levels of K48-linked polyubiquitinated α-synuclein in the brain samples of AS mice in comparison to wild-type animals. Finally, using an RT 2 Profiler PCR Array that analysed 84 genes specifically related to dopamine and serotonin pathways, we identified altered transcript level of various genes in the striatal tissues of AS mice that are commonly associated with nigrostriatal dysfunctions in Parkinson’s disease. These findings highlight α-synuclein as a novel target of Ube3a and suggest that α-synuclein pathology may contribute to the progressive motor and other behavioral abnormalities witnessed in AS mice.
2026-08-17 | Sleep disruption and neuropsychiatric features in Angelman syndrome: insights into underlying neurobiology.
Sleep disorders are a core feature of Angelman syndrome (AS), affecting approximately 80% of individuals. They typically manifest as insomnia and disrupted sleep-wake cycles and contribute substantially to the burden experienced by affected individuals and their families. AS is caused by loss of function of the ubiquitin protein ligase E3A (UBE3A) gene, which encodes the E3 ubiquitin ligase E6AP, a protein essential for synaptic development and function. In individuals with a maternal 15q11-q13 deletion, concomitant deletion of neighboring non-imprinted genes, including GABRB3, GABRA5, GABRG3, ATP10A, and HERC2, may also contribute to the phenotype. Evidence from animal models further indicates that UBE3A plays a key role in sleep homeostasis and circadian rhythm regulation, including through interactions with core clock genes such as BMAL1. In this narrative review, we examine the role of UBE3A in sleep regulation and outline the principal sleep disturbances observed in AS, integrating findings from both preclinical models and human studies, while also considering genotype-phenotype correlations for the main clinical manifestations. The available evidence suggests that sleep disruption may be closely linked to the core neurological and behavioral features of AS, particularly epilepsy and behavioral abnormalities, through shared pathophysiological mechanisms related to UBE3A deficiency. Early identification and management of sleep disturbances may therefore represent a potentially modifiable factor for improving behavioral outcomes, seizure control, and overall quality of life in individuals with AS. In addition, sleep measures should be considered as potentially relevant clinical endpoints in ongoing trials of emerging therapeutic strategies.
2026-07-31 | Comprehensive chemical and enantiomeric characterization of commercial turpentine oils by GC-MS.
Recent reports from families of individuals with Angelman syndrome (AS), a rare neurodevelopmental disorder characterised by severe neurological impairment and epilepsy, have described perceived neurological improvements following the topical application of a commercial turpentine oil (TO). These observations prompted the present analytical study, which aimed to characterise and quantify the terpenoid composition of 2 commercial TOs (Diamond and Creekwood), together with 6 additional commercial TOs, using gas chromatography-mass spectrometry (GC-MS). Analysis of 6 TOs reported to originate from Pinus pinaster revealed similar combined percentages of α- and β-pinene (≈75%), except for one oil that exhibited a more complex profile, a lower α-pinene content (≈30%), and the presence of eucalyptol, which is uncommon in TOs from this species. The Creekwood oil contained a higher proportion of α-pinene (≈76%) and a markedly lower β-pinene content (≈3%) than the Diamond oil (≈62% and ≈26%, respectively). Chiral GC-MS analysis further revealed contrasting enantiomeric distributions, with (-)-α-pinene predominating in the Diamond oil and (+)-α-pinene in the Creekwood oil, while (-)-β-pinene predominated in both samples. For quantitative analysis, the analytical method was successfully validated, demonstrating suitable detection (1.5-5.0 mg/L) and quantification (5.0-16.7 mg/L) limits, good linearity (r2>0.991), and acceptable precision and accuracy (<15%). These findings demonstrate substantial chemical variability among commercial TOs and provide a framework for future studies on the biological effects of pine resin terpenoids in neuronal models relevant to AS.
gene therapies
2026-09-24 | E3 Ubiquitin Ligases in Neurodevelopmental Disorders.
Neurodevelopmental disorders (NDDs) comprise a heterogeneous group of conditions that may present with developmental delay, intellectual disability, language impairment, epilepsy, autism-like features, motor abnormalities, or syndromic manifestations. Ubiquitination is an essential post-translational mechanism that regulates protein stability, localization, trafficking, and signaling. Because E3 ubiquitin ligases determine substrate specificity in this process, abnormalities in E3 ligases or E3-associated complexes can selectively affect proteins required for brain development and neuronal function. This review summarizes genetic and functional evidence linking E3 ubiquitin ligases, E3-complex components, substrate-recognition factors, and related ubiquitination regulators to NDDs. Gene Ontology enrichment analysis and mechanistic studies suggest that these genes converge on several major biological themes, including early neurodevelopment, neuronal migration, synaptic and circuit maturation, proteostasis, metabolism, and intracellular trafficking. However, the strength and translational relevance of the available evidence vary across genes. UBE3A-related Angelman syndrome currently provides the clearest example of mechanism-guided therapeutic development through UBE3A restoration and paternal allele reactivation. In contrast, many non-UBE3A mechanisms remain at the stage of pathway analysis, preclinical modulation, or candidate substrate validation. Future studies should clarify variant-specific functional effects, define direct disease-relevant substrates, and establish reproducible readouts that can support mechanism-based therapeutic development.
2026-07-04 | The SNRPN Bipartite Imprinting Centre in Region 15q11–q13 and Its Epigenetic Role in the Pursuit of a Cure for Angelman Syndrome
Angelman syndrome is a severe neurodevelopmental disorder arising from functional loss of the maternal allele of UBE3A, a gene that sits within a cluster of imprinted loci on the long arm of chromosome 15. Expression across this region is governed by a bipartite imprinting centre associated with the SNRPN gene, made up of two physically separated but functionally interdependent elements: the Prader–Willi syndrome smallest region of deletion overlap and the Angelman syndrome smallest region of deletion overlap. Together these elements establish, in the germline, and maintain, throughout somatic life, the parent-of-origin-specific expression pattern that distinguishes Angelman syndrome from its reciprocal disorder, Prader–Willi syndrome. Because the paternal copy of UBE3A remains structurally intact in most patients with Angelman syndrome, merely silenced by a long non-coding antisense transcript whose own expression is dictated by the imprinting centre, this locus has become the focal point of an unusually concentrated translational effort: rather than replacing a missing gene, contemporary therapeutic strategies aim to reverse an epigenetic mark and thereby unmask a dormant but functional allele. This review draws together the structural biology of the bipartite imprinting centre, the molecular events that establish and maintain its parent-specific epigenotype, the diagnostic and clinical consequences of its disruption, and the rapidly maturing pipeline of antisense oligonucleotides, small molecules, and genome- or epigenome-editing tools designed to exploit this biology therapeutically. Recent clinical trial data, including electroencephalographic and behavioural endpoints from antisense oligonucleotide programmes, are critically appraised alongside preclinical work on CRISPR-based epigenetic editing of the imprinting centre itself, an approach with the conceptual elegance of intervening at the very switch that imprinting biology depends upon. The review concludes that while no disease-modifying therapy is yet approved, the convergence of detailed mechanistic understanding of the SNRPN bipartite imprinting centre with scalable epigenetic editing technologies represents the most plausible route towards a transformative, rather than purely symptomatic, treatment for Angelman syndrome, while candidly addressing the developmental, safety and translational obstacles that remain.
2026-06-30 | Waking the Silent Gene in Angelman Syndrome
Angelman syndrome is a severe neurogenetic disorder characterised by developmental delay, motor impairment, absent or markedly limited speech, epilepsy and a characteristic happy demeanour with frequent laughter. It results from loss of function of the maternally inherited UBE3A gene located in the 15q11-q13 chromosomal region, while the paternal allele is normally epigenetically silenced in neurons by the long non-coding antisense transcript UBE3A-ATS. The estimated prevalence is approximately 1 in 15,000 to 1 in 20,000 individuals. Maternal chromosome 15 deletion accounts for approximately 70-75% of cases, whereas paternal uniparental disomy, imprinting defects and UBE3A sequence variants represent additional mechanisms. Diagnosis is generally established between 1 and 4 years of age through DNA methylation analysis and complementary molecular testing, when developmental delay, impaired balance and other clinical features become apparent. Current treatment remains supportive and multidisciplinary, including physiotherapy, occupational therapy, speech and augmentative communication support, seizure management, sleep regulation and assistive devices. This minireview summarises the genetic background of Angelman syndrome, present symptomatic therapy and emerging approaches designed to restore neuronal UBE3A activity. Particular attention is given to antisense oligonucleotides, including ION582, GTX-102 and rugonersen, as well as AAV-mediated gene replacement and CRISPR-Cas9-based gene-reactivation strategies. These approaches seek either to unsilence the paternal UBE3A allele or to deliver functional UBE3A to the nervous system. Although early clinical and preclinical findings are encouraging, none of the investigational strategies discussed here can yet be considered curative. Long-term evidence regarding efficacy, dosing, delivery, tolerability and safety remains essential before routine use in children with Angelman syndrome can be justified.
2026-05-15 | UBE3A Dosage Imbalance as a Molecular Framework Linking Angelman Syndrome and Dup15q-Associated Autism Phenotypes
UBE3A is a dosage-sensitive HECT E3 ubiquitin ligase whose neuronal expression is shaped by genomic imprinting at the 15q11.2–q13 locus. Opposite directions of UBE3A dosage imbalance contribute to distinct neurodevelopmental phenotypes: loss of maternal UBE3A underlies Angelman syndrome, whereas maternally derived duplications involving UBE3A contribute to Dup15q-associated syndromic autism phenotypes. This review synthesizes evidence across molecular architecture, isoform biology, neuronal imprinting, synaptic regulation, circuit excitability, and therapeutic development. The central argument is that UBE3A should not be interpreted as a general explanation for autism, but as a mechanistically informative model for a defined subset of neurodevelopmental disorders in which parent-of-origin effects and copy-number state are central. In Angelman syndrome, UBE3A loss disrupts proteostasis, synaptic plasticity, inhibitory circuit function, and neuronal excitability through distributed rather than single-pathway mechanisms. In maternal Dup15q syndrome, increased UBE3A dosage is strongly implicated in neuronal and synaptic abnormalities, although interval-wide dosage effects also contribute. Therapeutically, the direction of dosage change creates opposite translational requirements: restoration or paternal reactivation in Angelman syndrome versus dosage normalization in Dup15q-associated gain-of-function states. A dosage-directionality framework may therefore clarify how UBE3A biology connects molecular mechanism, developmental timing, and precision therapeutic design.
2026-05-15 | Nickase NmCas9 unsilences paternal Ube3a in a mouse model of Angelman syndrome without causing AAV vector integration.
Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by loss of maternal UBE3A. In neurons, the paternal (pat)UBE3A allele is silenced by a long non-coding antisense transcript called Ube3a-ATS. Previous genome-editing approaches used active nucleases to unsilence patUbe3a by disrupting Ube3a-ATS. However, these methods create DNA double-strand breaks (DSBs) and promote integration of adeno-associated virus (AAV) vector genomes, both of which raise potential safety concerns. Here, we found that a nickase Neisseria meningitidis Cas9 variant (nNmCas9-D15A) disrupted Ube3a-ATS transcription when targeted to the non-template strand and unsilenced patUbe3a in cultured mouse neurons without generating DSBs or causing AAV integration. Intracerebroventricular delivery of AAV9-nNmCas9-D15A in AS model mice potently and durably reduced Ube3a-ATS and elevated Ube3a throughout the cerebral cortex and hippocampus for at least 6 months. Further, this vector restored UBE3A expression in ~ 87% of cortical neurons, which compares favorably to previously reported efficiencies with active Cas9, dead Cas9, and zinc finger nuclease vectors. These results demonstrate that nNmCas9 is a highly effective and potentially safer genome editor for the treatment of AS.
oligonucleotides
2026-09-11 | Novel and Emerging Therapies for Childhood-Onset Movement Disorders.
Childhood-onset movement disorders comprise a heterogeneous group of rare conditions with substantial unmet therapeutic needs. Recent advances in disease gene discovery, mechanistic modeling, and translational platforms have accelerated the development of targeted therapies and enabled innovative clinical trial designs for small patient populations. To review novel and emerging therapies for childhood-onset movement disorders, with a focus on pharmacologic strategies, disease-modifying approaches, and patient-centered precision therapies. We surveyed the literature, major conference proceedings, and expert networks to identify therapies approved, in clinical development, or supported by compelling preclinical data between 2022 and 2025. We focused on small molecules and genetic therapies for conditions in which movement disorders represent a prominent clinical feature. Small molecules were categorized as repurposed or novel drugs, whereas genetic therapies included gene replacement, gene editing, and RNA-based expression modulation. Drug repurposing approaches have shown promise in disorders related to the GNAO1, ATP1A3, ATM, and ADCY5 genes. Novel small molecules have advanced for Friedreich's ataxia and Tourette's syndrome. Gene replacement therapies have demonstrated clinical benefit in select neurotransmitter disorders, whereas gene editing strategies have entered preclinical development for ATP1A3-related disease. Antisense oligonucleotide therapies have yielded encouraging early results across several conditions with prominent movement disorder phenotypes, including KIF1A-related neurological disorder, Angelman syndrome, SCN2A-related neurodevelopmental disorder, and ataxia-telangiectasia. Precision-based therapeutic strategies are rapidly reshaping the treatment landscape for childhood-onset movement disorders. Continued progress will depend on rigorous phenotyping, careful ethical oversight, and deliberate efforts to promote equitable global access to emerging therapies. © 2026 International Parkinson and Movement Disorder Society.
2026-07-14 | Emerging Therapies for Angelman Syndrome.
Angelman syndrome (AS) is a complex neurogenetic disorder characterized by severe global developmental delay, motor dysfunction, and epilepsy, primarily resulting from the lack of functional ubiquitin protein ligase E3A (UBE3A) protein expression in neurons. While current management remains largely symptomatic, the therapeutic landscape for AS is rapidly evolving. Emerging strategies aim to restore UBE3A function through upstream interventions, such as gene replacement therapy or unsilencing of the imprinted paternal allele, which is present but transcriptionally silenced in neurons due to genomic imprinting. This imprinting is mediated by the distal portion of a long non-coding RNA known as the UBE3A-antisense transcript (UBE3A-ATS). This UBE3A-ATS has become a key therapeutic target, with several approaches developed to unsilence the paternal allele, including antisense oligonucleotides (ASOs), CRISPR-based editing, synthetic microRNA, and other modalities. To date, three ASO programs have demonstrated promising signals in early clinical development, with reported improvements in clinical outcomes and electroencephalography (EEG) biomarkers. Given the potential for improved outcomes with early intervention, the inclusion of AS in broader genomic newborn screening programs is currently being explored. An early-intervention approach, or combination of approaches, holds significant promise for transforming the lives of individuals affected by AS with outcomes dependent on their age or genotype.
2026-03-22 | Emerging disease-modifying therapies for Angelman syndrome: A comprehensive review for pediatric neurologists.
Angelman syndrome (AS), a rare neurogenetic disorder affecting approximately 1 in 15,000 live births, results from loss of functional UBE3A gene expression and manifests with severe developmental delay, intellectual disability, absent speech, ataxia, epilepsy, and distinctive behavioral features. Until recently, only symptomatic management was available. This review provides pediatric neurologists with a comprehensive, practice-oriented overview of emerging disease-modifying therapies for AS, focusing on therapeutic approaches advancing through clinical development. The molecular pathophysiology of AS, natural history considerations critical for trial interpretation, and the current evidence for antisense oligonucleotide (ASO) therapies (ION582, GTX-102/apazunersen, rugonersen), gene replacement approaches (MVX-220), and next-generation strategies including CRISPR-based gene editing, artificial transcription factors, small molecules, and novel delivery platforms are reviewed. ASO therapies targeting the UBE3A antisense transcript represent the most clinically advanced approach, with three candidates showing proof-of-concept efficacy in Phase 1/2 studies and two advancing to pivotal Phase 3 trials. Gene replacement therapy offers potential single-administration treatment but faces challenges regarding safety, immune responses, and durability. Next-generation approaches including CRISPR activation, epigenetic editing, and blood-brain barrier-penetrating delivery systems show preclinical promise. Critical challenges include outcome measurement limitations, genotype stratification, long-term safety monitoring, and ensuring equitable access. These advances herald a transformation in AS clinical care and represent a milestone in precision pediatric neurology.
2026-03-01 | A xenotransplantation model for reactivation of paternal UBE3A using human-specific antisense oligonucleotides.
For many neurodevelopmental disorders, genetic treatment discovery is complicated by non-homology between human and non-human model system genomes. Antisense oligonucleotides (ASOs) influence protein expression by sequence-specific binding of RNA, resulting in targeted degradation or alternative splicing, and thereby provide a promising avenue for clinical therapeutics. Angelman Syndrome (AS), caused by loss-of-function of maternal UBE3A, has emerged as a monogenic neurodevelopmental disorder for which ASO therapy might be particularly amenable due to genomic imprinting. In an AS mouse model, Ube3a reactivation of the paternal allele using ASOs has been previously shown to rescue disease-relevant phenotypes. However, the poor sequence homology between murine and human UBE3A-ATS requires a human model system for screening of ASOs with clinical therapeutic potential. Here we evaluate an ASO targeting UBE3A-ATS using human induced pluripotent stem cell (hiPSC)-derived AS neurons in vitro and in vivo. We assessed the effect of ASO-treatment on cultured AS patient hiPSC-derived neurons through protein and RNA expression analysis. To increase clinical translatability, we designed a platform to evaluate this ASO in vivo by xenotransplantation of hiPSC-derived AS neurons into the brains of neonatal mice, with intracerebroventricular administration of the UBE3A-ATS ASO three weeks later. One week after ASO treatment, we observed in vivo reinstatement of UBE3A expression in xenotransplanted human neurons. These results highlight the potential for a versatile platform to evaluate efficacy of human-specific ASOs, for which AS provides an instructive proof-of-concept for therapeutic reactivation of UBE3A.
2026-02-03 | A dual-reporter mouse for therapeutic discovery in Angelman syndrome.
Angelman syndrome is a neurodevelopmental disorder caused by loss of the maternal UBE3A allele, the sole source of UBE3A in mature neurons owing to epigenetic silencing of the paternal allele. Although emerging therapies are being developed to restore UBE3A expression by activating the dormant paternal UBE3A allele, existing mouse models for such preclinical studies have limited throughput and utility, creating bottlenecks for both in vitro therapeutic screening and in vivo characterization. To address this, we developed the Ube3a-INSG dual-reporter knockin mouse, in which an IRES-Nanoluciferase-T2A-Sun1-sfGFP (INSG) cassette was inserted downstream of the endogenous Ube3a stop codon. The INSG model preserves UBE3A protein levels and function while enabling 2 complementary allele-specific readouts: Sun1-sfGFP and Nanoluciferase. We show that Sun1-sfGFP, a nuclear envelope-localized reporter, enables single-cell fluorescence analysis, whole-brain light-sheet imaging, and nuclear quantification by flow cytometry. Further, Nanoluciferase supports high-throughput luminescence assays for sensitive pharmacological profiling in cultured neurons and noninvasive in vivo bioluminescence imaging for pharmacodynamic assessment. By combining scalable screening, cellular analysis, and real-time in vivo monitoring in a single model, the Ube3a-INSG dual-reporter mouse provides a powerful platform to accelerate therapeutic development centered on UBE3A.
proteins
2026-09-29 | Phenotyping iPSC-derived neurons from Angelman patients and partial rescue via JNK pathway inactivation.
Angelman Syndrome (AS, MIM #105,830) is a rare neurodevelopmental disorder caused by imprinting defects, and it is marked by motor impairment, intellectual disability, speech limitations, and seizures. The condition arises due to the loss of function in neurons of the maternally-inherited UBE3A gene, mapping in the imprinted chromosomal region 15q11.2-q13, through a variety of genetic and epigenetic mechanisms. UBE3A encodes a ubiquitin E3 ligase, which is essential for synaptic plasticity. Most studies of AS have been performed on animal models, while induced pluripotent stem cells (IPSCs), mainly generated from patients with deletion, remain limited in number. Here we report on the generation and characterization of human cortical neurons derived from IPSCs obtained from children representative of the main AS genotypes: 3 with 15q11-13 deletion, 3 with UBE3A mutations, 3 with uniparental disomy, and 2 with imprinting defects. During early neuronal differentiation, morphological analyses highlighted a reduced dendritic branching and an increased number of thin filopodia, while migration assays revealed reduced neurite mobility in AS human neurons with the most severe genetic defect, namely the 15q11-13 deletion. At a later differentiation time point, electrophysiological analyses revealed impaired neuronal activity in AS patient-derived neurons. To investigate pathways potentially involved in synaptic dysfunction, we examined the JNK (c-Jun N-terminal kinase) signalling pathway, which plays key roles in neuroinflammation and synaptic development. We found increased JNK activation and, importantly, treatment with a JNK-inhibitor, D-JNKI1, partially rescued the neuronal morphological defects, significantly reducing the number of immature protrusions, as well as defects in electrophysiological properties. Our patient-specific models contribute elucidate how loss of UBE3A leads to aberrant neuronal maturation and function in the precocious stages of neuronal development and how treatment with D-JNKI1 may pave the way for new therapeutic possibilities.
2026-02-09 | Advances and challenges of precision epigenetic therapy in treating genomic imprinting diseases.
Genomic imprinting disorders (IDs) arise from the disruption of parent-of-origin-specific gene expression, a process governed by heritable epigenetic marks. Conventional therapies are largely symptomatic and fail to correct the underlying defect in dynamic gene regulation. Epigenome editing, using programmable DNA-targeting tools to rewrite epigenetic information, has emerged as a powerful therapeutic strategy that directly addresses this molecular pathology. This review synthesizes the transformative progress of the past decade, arguing that epigenome editing is poised to revolutionize the treatment of these conditions. We detail key breakthroughs in both editor design and in vivo delivery. These include the development of next-generation editors, such as compact "hit-and-run" systems that establish durable epigenetic memory after only transient expression-a critical feature for clinical safety. We then examine parallel advances in delivery platforms, including engineered adeno-associated virus (AAV) vectors with enhanced central nervous system (CNS) tropism and programmable lipid nanoparticles (LNPs) for precise extra-hepatic targeting. The therapeutic potential of combining these technologies is underscored by convincing preclinical data in models of Angelman (AS) and Prader-Willi syndromes (PWS), where the targeted rewriting of epigenetic marks has successfully reactivated silenced alleles and rescued disease-relevant phenotypes. Finally, we discuss the remaining challenges-including long-term durability and off-target safety-that must be overcome to translate this scientific potential into transformative medicines.
2025-09-16 | Structural analysis of HERC2/UBE3A and HERC2/DOCK10 complexes provides new insights into the molecular basis of Angelman, Angelman-like and Dup15q Syndromes
UBE3A and HERC2 are two mutually interacting HECT E3 Ubiquitin ligases whose genes are altered in 15q11.2-13.1 Duplication (Dup15q) Syndrome, Angelman Syndrome (AS) and other phenotypically-related mental retardation syndromes. Using quantitative binding assays, X-ray crystallography and sequence conservation analysis, we show that the HERC2/UBE3A complex occurs in probably most animals with a central nervous system, via a conserved interface involving the RLD2 domain of HERC2 and a "DxDKDxD" motif of UBE3A. We found that HERC2 also recognizes and binds to similar DxDKDxD motifs within a handful of other proteins relevant to brain development (DOCK10, PCM1, USP35, BAZ2B, ARID4A, ARIP4, RERE and MYT1). We further investigated the interaction of HERC2 with DOCK10, a RAC1- and CDC42-GEF protein that regulates dendritic spine morphogenesis in hippocampal neurons. Both disruption of the HERC2-binding motif in DOCK10 and knockdown of HERC2 affected the GEF activity of DOCK10. We also show that the DOCK10-induced dendritic spine formation is dependent on its ability to bind HERC2. Structural modeling of full-length DOCK10, free or bound to either RLD2, CDC42 or RAC1 indicates that the GEF activation of full-length DOCK10 requires a conformational change that is stimulated by binding to HERC2. Based on our data, we propose that under pathological conditions, in developing brains with an abnormal dosage of either HERC2 or its dominant partner UBE3A, increased or decreased amounts of HERC2/DOCK10 complexes could lead to altered GTPase activation. This in turn could affect dendritic spine formation and neurodevelopment.
2025-07-14 | A Human Angelman Syndrome Class II Pluripotent Stem Cell line with Fluorescent Paternal UBE3A Reporter
Abstract Introduction Angelman Syndrome (AS) is characterized in large part by the loss of functional UBE3A protein in mature neurons. A majority of AS etiologies is linked to deletion of the maternal copy of the UBE3A gene and epigenetic silencing of the paternal copy. A common therapeutic strategy is to unsilence the intact paternal copy thereby restoring UBE3A levels. Identifying novel therapies has been aided by a UBE3A-YFP reporter mouse model. This study presents an analogous fluorescent UBE3A reporter system in human cells. Methods Previously derived induced Pluripotent Stem Cells (iPSCs) with a Class II large deletion at the UBE3A locus are used in this study. mGL and eGFP are integrated downstream of the endogenous UBE3A using CRISPR/Cas9. These reporter iPSCs are differentiated into 2D and 3D neural cultures to monitor long-term neuronal maturation. Green fluorescence dynamics are analyzed by immunostaining and flow cytometry. Results The reporter is successfully integrated into the genome and reports paternal UBE3A expression. Fluorescence expression gradually reduces with UBE3A silencing in neurons as they mature. Expression patterns also reflect expected responses to molecules known to reactivate paternal UBE3A . Discussion This human-cell-based model can be used to screen novel therapeutic candidates, facilitate tracking of UBE3A expression in time and space, and study human-specific responses. However, its ability to restore UBE3A function cannot be studied using this model. Further research in human cells is needed to engineer systems with functional UBE3A to fully capture the therapeutic capabilities of novel candidates.
2025-03-18 | The gain-of-function UBE3AQ588E variant causes Angelman-like neurodevelopmental phenotypes in mice.
Mutations in the E3 ubiquitin ligase UBE3A that cause enzymatic gain-of-function result in disease phenotypes which differ from classic Angelman syndrome. However, these phenotypes are highly heterogeneous raising questions about the mechanistic basis of such phenotypic diversity. Here, we characterize a mouse model harboring a Ube3aQ606E gain of function variant (UBE3AQ588E in humans). Extensive behavioral phenotyping showed that animals possessing a maternally inherited mutation (Ube3amQ606E) paradoxically show many behavioral deficits indicative of overall UBE3A loss-of-function. These included pronounced motor deficits, hypoactivity, and reduced stereotypic behaviors. Moreover, brain weights and MRI analysis revealed global microcephaly with a postnatal onset, consistent with phenotypes described in Angelman syndrome model mice. Additional biochemical analyses demonstrated an increased abundance of UBE3A substrates in brain tissue and immunofluorescence analyses showed that microcephaly is not caused by increased apoptotic cell death. Together, our results strongly suggest a novel mechanism by which the Ube3amQ606E mutation leads to enhanced self-targeted degradation of UBE3A, leading to an overall loss of enzyme activity, resulting in Angelman-like phenotypes in vivo.
other
2026-01-01 | Generation of human pineal gland organoids with melatonin production for disease modeling.
The pineal gland regulates circadian rhythms through melatonin production, yet human studies are limited by poor tissue access. To overcome this, we developed human pineal gland organoids (hPGOs) from pluripotent stem cells, modeling pineal development and function. Single-cell RNA sequencing revealed distinct mature and developing pinealocyte populations with transcriptomic profiles closely resembling the in vivo pineal gland. hPGOs produce melatonin, express adrenergic receptors, and respond to noradrenaline, mimicking physiological regulation. To model disease-related impairments, we generated hPGOs from Angelman syndrome (AS) patient-derived iPSCs, which exhibit disrupted pinealocyte differentiation and markedly reduced melatonin synthesis, reflecting AS-related developmental pathology. Additionally, transplanted hPGOs restored circulating melatonin in pinealectomized mice, demonstrating their potential for cell-therapy approaches. These findings establish hPGOs as a robust platform for probing pineal development, circadian regulation, and their disruption in neurodevelopmental and sleep-related disorders.
2025-12-18 | Extracellular vesicle dysfunction contributes to synaptic and cognitive deficits in a mouse model of Angelman syndrome.
Angelman syndrome (AS) is a devastating neurodevelopmental disorder caused by deficiency of the maternally inherited UBE3A. It is characterized by severe cognitive impairment, motor dysfunction, seizures, and developmental delays. Several mouse models of AS reproduce these debilitating features, including impaired memory function and synaptic plasticity, reduced dendritic spine density, and lysosomal alterations. Emerging research highlights the critical role of extracellular vesicles (EVs) in brain development and function, with growing evidence linking EV dysregulation to various neurological disorders. In this study, we first compared key features of EVs between wild-type (WT) and AS mice. EV secretion from forebrain synaptosomes was impaired in AS mice as compared to WT. Importantly, Ube3a was detected in EVs released from WT forebrain synaptosomes, suggesting a role for Ube3a in neuronal communication. We then identified TRPML1, a lysosomal ion channel, as a regulator of EV release and uptake, unveiling a novel molecular mechanism underlying EV dynamics. Furthermore, treatment with WT neuron-derived EVs significantly improved dendritic and spine morphology of cultured hippocampal neurons prepared from AS mice. Remarkably, systemic administration of WT brain-derived EVs restored hippocampal neuronal morphology and improved learning and memory in AS mice. These findings not only enhance our understanding of AS pathophysiology but also support EVs as a promising strategy for treating this currently incurable disorder.
2025-08-07 | Stem-cell modeling of cerebellar dysfunction of Angelman syndrome
Abstract Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function of the maternal allele of the neuron-specific imprinted gene UBE3A . Although AS presents with developmental delay, ataxia, epilepsy, and speech impairment, the distinct roles of various brain regions in its pathology remain unclear, hindering the design of effective therapeutic strategies. Of all brain regions, the nature and impact of dysfunction of the cerebellum in AS remain elusive. To start addressing this, we leveraged our optimized stem cell-based model of regionally patterned human cerebellar organoids (hCerOs) capable of producing major cerebellar neuronal subtypes, including Purkinje and granule cells, further matured in a two-dimensional (2D) culture system. We modeled AS using induced pluripotent stem cell (iPSC) lines carrying the common class II deletion and unaffected controls previously validated in our system. hCerOs from both backgrounds recapitulate lineage commitment and neuron-specific UBE3A imprinting. AS hCerOs consistently show reduced size, impaired neuroepithelial expansion, and diminished expression of glutamatergic and GABAergic progenitor markers. Transcriptomic profiling and functional assays assessing neuronal activity during the maturation stage uncovered delayed maturation, abnormal firing and increased neuronal excitability in AS cultures. These results position our hCerO model as a robust platform for future mechanistic studies and therapeutic screening aimed at targeting cerebellar dysfunction in AS.
2024-09-24 | Functional Recovery in Severe Genetic Syndromes: Clinical Experience of Cell Therapy in Angelman Syndrome
Genetic pathologies remain a major challenge in modern medicine, although medical technologies, laboratory diagnostics, and targeted therapy tools have significantly developed and expanded. Since etiopathogenetic therapy is not provided, children with genetic disorders receive only symptomatic treatment stabilizing their status and mitigating life-threatening factors, but not contributing to even a partially functional recovery of damaged organs. Angelman syndrome is a rare and severe genetic pathology characterized by delayed psychomotor development, seizures, and conduct disorders. Patients with this diagnosis have, in general, a poor prognosis for development and socialization. Stem cell transplantation is a promising approach to treating various genetic, neurodegenerative, and autoimmune diseases. The article describes two clinical cases of patients with verified Angelman syndrome who received a combination therapy with stem cell transplantation as a key method. Health outcomes were analyzed using the data of physical examination, assessment of neurological and psychological statuses, testing methods of neuroimaging and functional medicine, and laboratory testing of hormonal, mitochondrial, immune states of patients. The results showed a significant improvement in patients’ psychomotor development and a positive dynamic in laboratory and functional indicators. Therefore, the studied combination therapy approach could become a promising method for treating patients with severe genetic diseases accompanied by serious nervous system damage.
2023-12-15 | Exosomes from WT Mice Enhances Memory Recall-induced IEG Expression and Rescue Dendritic Spines Deficit in Angelman Syndrome Mice
Angelman syndrome (AS) is a rare neurogenetic disorder caused by deletion or mutations in the UBE3A gene, which lead to the deficiency of the UBE3A protein in neurons. UBE3A is crucial for normal neuronal communication, as it regulates the turnover of synaptic proteins and synaptic plasticity. Exosomes, small extracellular vesicles released by various cells, including neurons, play important roles in intercellular communication. Exosomes contain a variety of molecules, including proteins and nucleic acids, and can transfer these components between cells. Emerging evidence indicates that exosomes are critical for normal brain functions, and in recent years many studies have investigated the therapeutic potential of exosomes as vehicles for delivering therapeutic cargoes in various neurological disorders. In this study, we investigated the potential role of exosomes in regulating spine morphology in AS mice. Our results showed that activation of the lysosomal calcium channel TRPML1 stimulated exosome release from synaptosomes prepared from adult WT mice, but not from synaptosomes prepared from adult AS mice. Intriguingly, UBE3A was present in exosomes secreted from WT mice. It has been previously shown that hippocampal neurons of AS mice exhibit fewer dendritic spines, as compared to those from WT mice. Incubation of cultured hippocampal neurons from AS mice with conditioned medium from cultured hippocampal neurons from WT mice rescued the number of dendritic spines. Our data suggest that this effect is most likely due to exosomes in the medium, since purified exosomes from conditioned medium of WT neurons produced a similar rescue effect in cultured neurons from AS mice. Moreover, intravenous injection of exosomes prepared from synaptosomes of adult WT mice seemed to enhance contextual memory recall and associated immediate early gene (IEG) expression, and te number of dendritic spines in CA1 pyramidal neurons in adult AS mice. Whether and to what degree UBE3A present in WT exosomes participates in the rescue of AS neuronal morphology remains to be determined. Together, these results reveal both altered exosomal secretion and composition in AS mice. Treatment of AS neurons or adult AS mice with exosomes rescued dendritic spine deficits in vitro and in vivo. These results open new therapeutical approaches for using exosomes as a potential treatment for this disease.
small molecules
2026-09-24 | Parvalbumin interneurons and dentate gyrus homeostatic dysregulation shape epileptogenesis in Angelman syndrome model mice.
Understanding how neural circuits transition from seizure-resistant to seizure-prone is essential for developing improved epilepsy therapies. Here, we study this process by leveraging the heightened susceptibility to seizure kindling of Angelman syndrome (AS) model mice, which lack the maternal Ube3a (mUbe3a) allele. We identify parvalbumin-expressing (PV+) interneurons as critical gatekeepers; selective mUbe3a deletion in PV+ neurons phenocopies enhanced AS epileptogenesis, whereas restoring UBE3A broadly in GABAergic neurons confers seizure resistance. Further, pathological remodeling of the extracellular matrix in the dentate gyrus faithfully tracks with post-kindling seizure susceptibility, highlighting this region's particular relevance to enhanced epileptogenesis. Mechanistically, we uncover a 'two-hit' electrophysiologic phenomenon in AS model mice: kindling fails to recruit compensatory inhibition onto dentate granule cells and instead drives their maladaptive intrinsic hyperexcitability. Together, these findings link cell type-specific inhibitory dysfunction and altered homeostatic plasticity to epileptogenesis, suggesting future circuit-based treatment strategies.
2026-09-22 | Treatment responses to antiseizure medication in children with Angelman syndrome.
Angelman Syndrome (AS) is a rare neurodevelopmental disorder with epilepsy affecting up to 90% of the children. Although several studies have examined antiseizure medications (ASMs) in children with AS, preferred ASMs vary between countries and while new ASMs have become available in clinical practice in recent years, their impact on epilepsy treatment in children with AS remains unclear. We report on the frequency of most prescribed ASMs, responder rates and rate of severe side effects of ASM in a natural history cohort. Epilepsy and epilepsy-related parameters were analyzed including differences between genetic subgroups. A total of 101 children with AS who visited the Angelman center Munich between 2019 and first quarter of 2025 were included in this retrospective analysis. Epilepsy characteristics, frequency of prescribed ASMs, responder rate and severe side effect rate were recorded. Epilepsy was present in 75%, with a higher incidence in the deletion genotype. Most patients experienced seizures rather rarely, but one in five had daily or weekly seizures. Seizure frequency was higher in early childhood. Therapy-refractory epilepsy was observed in 34% of AS children with epilepsy. Rate of therapy-refractory epilepsy and seizure burden was higher in the deletion group. Among the most prescribed ASMs (ethosuximide, levetiracetam and valproate), ethosuximide and valproate demonstrated the highest responder rate (>50% reduction of seizures) in 78% and 75% of patients, respectively, closely followed by levetiracetam (64%). The reported side effect rate of ASM did not differ between the most prescribed medications. The three most prescribed ASMs (valproate, ethosuximide and levetiracetam) in our cohort showed high responder rates in children with Angelman Syndrome. Overall seizure burden and rates of therapy-refractory epilepsy were lower than previously reported, suggesting that combining new and established ASMs may improve seizure outcomes in this population.
2026-09-03 | Aberrant accumulation of α-synuclein might be linked with the progressive motor deficits in a mouse model of Angelman syndrome
Summary Dysfunction of maternal UBE3A leads to Angelman syndrome (AS), which is characterized by significant intellectual and motor debilities. However, the molecular underpinnings of the behavioral deficits associated with UBE3A dysfunction remain obscure. In this study, we utilized a model mouse of AS and report, for the first time, that the aberrant accumulation of α-synuclein may be linked to the development of AS. Firstly, we demonstrated a progressive deterioration of various motor functions in AS mice beginning from the early adolescent phase. Subsequently, we observed an age-dependent increase in the accumulation of both soluble and insoluble α-synuclein, including its pathological variant (pSer129), in the striatum and substantia nigra dopaminergic neurons of AS mice. We also found that Ube3a interacts with α-synuclein and promotes its proteasome-mediated degradation, as evidenced by decreased levels of K48-linked polyubiquitinated α-synuclein in the brain samples of AS mice in comparison to wild-type animals. Finally, using an RT 2 Profiler PCR Array that analysed 84 genes specifically related to dopamine and serotonin pathways, we identified altered transcript level of various genes in the striatal tissues of AS mice that are commonly associated with nigrostriatal dysfunctions in Parkinson’s disease. These findings highlight α-synuclein as a novel target of Ube3a and suggest that α-synuclein pathology may contribute to the progressive motor and other behavioral abnormalities witnessed in AS mice.
2026-08-17 | Sleep disruption and neuropsychiatric features in Angelman syndrome: insights into underlying neurobiology.
Sleep disorders are a core feature of Angelman syndrome (AS), affecting approximately 80% of individuals. They typically manifest as insomnia and disrupted sleep-wake cycles and contribute substantially to the burden experienced by affected individuals and their families. AS is caused by loss of function of the ubiquitin protein ligase E3A (UBE3A) gene, which encodes the E3 ubiquitin ligase E6AP, a protein essential for synaptic development and function. In individuals with a maternal 15q11-q13 deletion, concomitant deletion of neighboring non-imprinted genes, including GABRB3, GABRA5, GABRG3, ATP10A, and HERC2, may also contribute to the phenotype. Evidence from animal models further indicates that UBE3A plays a key role in sleep homeostasis and circadian rhythm regulation, including through interactions with core clock genes such as BMAL1. In this narrative review, we examine the role of UBE3A in sleep regulation and outline the principal sleep disturbances observed in AS, integrating findings from both preclinical models and human studies, while also considering genotype-phenotype correlations for the main clinical manifestations. The available evidence suggests that sleep disruption may be closely linked to the core neurological and behavioral features of AS, particularly epilepsy and behavioral abnormalities, through shared pathophysiological mechanisms related to UBE3A deficiency. Early identification and management of sleep disturbances may therefore represent a potentially modifiable factor for improving behavioral outcomes, seizure control, and overall quality of life in individuals with AS. In addition, sleep measures should be considered as potentially relevant clinical endpoints in ongoing trials of emerging therapeutic strategies.
2026-07-31 | Comprehensive chemical and enantiomeric characterization of commercial turpentine oils by GC-MS.
Recent reports from families of individuals with Angelman syndrome (AS), a rare neurodevelopmental disorder characterised by severe neurological impairment and epilepsy, have described perceived neurological improvements following the topical application of a commercial turpentine oil (TO). These observations prompted the present analytical study, which aimed to characterise and quantify the terpenoid composition of 2 commercial TOs (Diamond and Creekwood), together with 6 additional commercial TOs, using gas chromatography-mass spectrometry (GC-MS). Analysis of 6 TOs reported to originate from Pinus pinaster revealed similar combined percentages of α- and β-pinene (≈75%), except for one oil that exhibited a more complex profile, a lower α-pinene content (≈30%), and the presence of eucalyptol, which is uncommon in TOs from this species. The Creekwood oil contained a higher proportion of α-pinene (≈76%) and a markedly lower β-pinene content (≈3%) than the Diamond oil (≈62% and ≈26%, respectively). Chiral GC-MS analysis further revealed contrasting enantiomeric distributions, with (-)-α-pinene predominating in the Diamond oil and (+)-α-pinene in the Creekwood oil, while (-)-β-pinene predominated in both samples. For quantitative analysis, the analytical method was successfully validated, demonstrating suitable detection (1.5-5.0 mg/L) and quantification (5.0-16.7 mg/L) limits, good linearity (r2>0.991), and acceptable precision and accuracy (<15%). These findings demonstrate substantial chemical variability among commercial TOs and provide a framework for future studies on the biological effects of pine resin terpenoids in neuronal models relevant to AS.
gene therapies
2026-09-24 | E3 Ubiquitin Ligases in Neurodevelopmental Disorders.
Neurodevelopmental disorders (NDDs) comprise a heterogeneous group of conditions that may present with developmental delay, intellectual disability, language impairment, epilepsy, autism-like features, motor abnormalities, or syndromic manifestations. Ubiquitination is an essential post-translational mechanism that regulates protein stability, localization, trafficking, and signaling. Because E3 ubiquitin ligases determine substrate specificity in this process, abnormalities in E3 ligases or E3-associated complexes can selectively affect proteins required for brain development and neuronal function. This review summarizes genetic and functional evidence linking E3 ubiquitin ligases, E3-complex components, substrate-recognition factors, and related ubiquitination regulators to NDDs. Gene Ontology enrichment analysis and mechanistic studies suggest that these genes converge on several major biological themes, including early neurodevelopment, neuronal migration, synaptic and circuit maturation, proteostasis, metabolism, and intracellular trafficking. However, the strength and translational relevance of the available evidence vary across genes. UBE3A-related Angelman syndrome currently provides the clearest example of mechanism-guided therapeutic development through UBE3A restoration and paternal allele reactivation. In contrast, many non-UBE3A mechanisms remain at the stage of pathway analysis, preclinical modulation, or candidate substrate validation. Future studies should clarify variant-specific functional effects, define direct disease-relevant substrates, and establish reproducible readouts that can support mechanism-based therapeutic development.
2026-07-04 | The SNRPN Bipartite Imprinting Centre in Region 15q11–q13 and Its Epigenetic Role in the Pursuit of a Cure for Angelman Syndrome
Angelman syndrome is a severe neurodevelopmental disorder arising from functional loss of the maternal allele of UBE3A, a gene that sits within a cluster of imprinted loci on the long arm of chromosome 15. Expression across this region is governed by a bipartite imprinting centre associated with the SNRPN gene, made up of two physically separated but functionally interdependent elements: the Prader–Willi syndrome smallest region of deletion overlap and the Angelman syndrome smallest region of deletion overlap. Together these elements establish, in the germline, and maintain, throughout somatic life, the parent-of-origin-specific expression pattern that distinguishes Angelman syndrome from its reciprocal disorder, Prader–Willi syndrome. Because the paternal copy of UBE3A remains structurally intact in most patients with Angelman syndrome, merely silenced by a long non-coding antisense transcript whose own expression is dictated by the imprinting centre, this locus has become the focal point of an unusually concentrated translational effort: rather than replacing a missing gene, contemporary therapeutic strategies aim to reverse an epigenetic mark and thereby unmask a dormant but functional allele. This review draws together the structural biology of the bipartite imprinting centre, the molecular events that establish and maintain its parent-specific epigenotype, the diagnostic and clinical consequences of its disruption, and the rapidly maturing pipeline of antisense oligonucleotides, small molecules, and genome- or epigenome-editing tools designed to exploit this biology therapeutically. Recent clinical trial data, including electroencephalographic and behavioural endpoints from antisense oligonucleotide programmes, are critically appraised alongside preclinical work on CRISPR-based epigenetic editing of the imprinting centre itself, an approach with the conceptual elegance of intervening at the very switch that imprinting biology depends upon. The review concludes that while no disease-modifying therapy is yet approved, the convergence of detailed mechanistic understanding of the SNRPN bipartite imprinting centre with scalable epigenetic editing technologies represents the most plausible route towards a transformative, rather than purely symptomatic, treatment for Angelman syndrome, while candidly addressing the developmental, safety and translational obstacles that remain.
2026-06-30 | Waking the Silent Gene in Angelman Syndrome
Angelman syndrome is a severe neurogenetic disorder characterised by developmental delay, motor impairment, absent or markedly limited speech, epilepsy and a characteristic happy demeanour with frequent laughter. It results from loss of function of the maternally inherited UBE3A gene located in the 15q11-q13 chromosomal region, while the paternal allele is normally epigenetically silenced in neurons by the long non-coding antisense transcript UBE3A-ATS. The estimated prevalence is approximately 1 in 15,000 to 1 in 20,000 individuals. Maternal chromosome 15 deletion accounts for approximately 70-75% of cases, whereas paternal uniparental disomy, imprinting defects and UBE3A sequence variants represent additional mechanisms. Diagnosis is generally established between 1 and 4 years of age through DNA methylation analysis and complementary molecular testing, when developmental delay, impaired balance and other clinical features become apparent. Current treatment remains supportive and multidisciplinary, including physiotherapy, occupational therapy, speech and augmentative communication support, seizure management, sleep regulation and assistive devices. This minireview summarises the genetic background of Angelman syndrome, present symptomatic therapy and emerging approaches designed to restore neuronal UBE3A activity. Particular attention is given to antisense oligonucleotides, including ION582, GTX-102 and rugonersen, as well as AAV-mediated gene replacement and CRISPR-Cas9-based gene-reactivation strategies. These approaches seek either to unsilence the paternal UBE3A allele or to deliver functional UBE3A to the nervous system. Although early clinical and preclinical findings are encouraging, none of the investigational strategies discussed here can yet be considered curative. Long-term evidence regarding efficacy, dosing, delivery, tolerability and safety remains essential before routine use in children with Angelman syndrome can be justified.
2026-05-15 | UBE3A Dosage Imbalance as a Molecular Framework Linking Angelman Syndrome and Dup15q-Associated Autism Phenotypes
UBE3A is a dosage-sensitive HECT E3 ubiquitin ligase whose neuronal expression is shaped by genomic imprinting at the 15q11.2–q13 locus. Opposite directions of UBE3A dosage imbalance contribute to distinct neurodevelopmental phenotypes: loss of maternal UBE3A underlies Angelman syndrome, whereas maternally derived duplications involving UBE3A contribute to Dup15q-associated syndromic autism phenotypes. This review synthesizes evidence across molecular architecture, isoform biology, neuronal imprinting, synaptic regulation, circuit excitability, and therapeutic development. The central argument is that UBE3A should not be interpreted as a general explanation for autism, but as a mechanistically informative model for a defined subset of neurodevelopmental disorders in which parent-of-origin effects and copy-number state are central. In Angelman syndrome, UBE3A loss disrupts proteostasis, synaptic plasticity, inhibitory circuit function, and neuronal excitability through distributed rather than single-pathway mechanisms. In maternal Dup15q syndrome, increased UBE3A dosage is strongly implicated in neuronal and synaptic abnormalities, although interval-wide dosage effects also contribute. Therapeutically, the direction of dosage change creates opposite translational requirements: restoration or paternal reactivation in Angelman syndrome versus dosage normalization in Dup15q-associated gain-of-function states. A dosage-directionality framework may therefore clarify how UBE3A biology connects molecular mechanism, developmental timing, and precision therapeutic design.
2026-05-15 | Nickase NmCas9 unsilences paternal Ube3a in a mouse model of Angelman syndrome without causing AAV vector integration.
Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by loss of maternal UBE3A. In neurons, the paternal (pat)UBE3A allele is silenced by a long non-coding antisense transcript called Ube3a-ATS. Previous genome-editing approaches used active nucleases to unsilence patUbe3a by disrupting Ube3a-ATS. However, these methods create DNA double-strand breaks (DSBs) and promote integration of adeno-associated virus (AAV) vector genomes, both of which raise potential safety concerns. Here, we found that a nickase Neisseria meningitidis Cas9 variant (nNmCas9-D15A) disrupted Ube3a-ATS transcription when targeted to the non-template strand and unsilenced patUbe3a in cultured mouse neurons without generating DSBs or causing AAV integration. Intracerebroventricular delivery of AAV9-nNmCas9-D15A in AS model mice potently and durably reduced Ube3a-ATS and elevated Ube3a throughout the cerebral cortex and hippocampus for at least 6 months. Further, this vector restored UBE3A expression in ~ 87% of cortical neurons, which compares favorably to previously reported efficiencies with active Cas9, dead Cas9, and zinc finger nuclease vectors. These results demonstrate that nNmCas9 is a highly effective and potentially safer genome editor for the treatment of AS.
oligonucleotides
2026-09-11 | Novel and Emerging Therapies for Childhood-Onset Movement Disorders.
Childhood-onset movement disorders comprise a heterogeneous group of rare conditions with substantial unmet therapeutic needs. Recent advances in disease gene discovery, mechanistic modeling, and translational platforms have accelerated the development of targeted therapies and enabled innovative clinical trial designs for small patient populations. To review novel and emerging therapies for childhood-onset movement disorders, with a focus on pharmacologic strategies, disease-modifying approaches, and patient-centered precision therapies. We surveyed the literature, major conference proceedings, and expert networks to identify therapies approved, in clinical development, or supported by compelling preclinical data between 2022 and 2025. We focused on small molecules and genetic therapies for conditions in which movement disorders represent a prominent clinical feature. Small molecules were categorized as repurposed or novel drugs, whereas genetic therapies included gene replacement, gene editing, and RNA-based expression modulation. Drug repurposing approaches have shown promise in disorders related to the GNAO1, ATP1A3, ATM, and ADCY5 genes. Novel small molecules have advanced for Friedreich's ataxia and Tourette's syndrome. Gene replacement therapies have demonstrated clinical benefit in select neurotransmitter disorders, whereas gene editing strategies have entered preclinical development for ATP1A3-related disease. Antisense oligonucleotide therapies have yielded encouraging early results across several conditions with prominent movement disorder phenotypes, including KIF1A-related neurological disorder, Angelman syndrome, SCN2A-related neurodevelopmental disorder, and ataxia-telangiectasia. Precision-based therapeutic strategies are rapidly reshaping the treatment landscape for childhood-onset movement disorders. Continued progress will depend on rigorous phenotyping, careful ethical oversight, and deliberate efforts to promote equitable global access to emerging therapies. © 2026 International Parkinson and Movement Disorder Society.
2026-07-14 | Emerging Therapies for Angelman Syndrome.
Angelman syndrome (AS) is a complex neurogenetic disorder characterized by severe global developmental delay, motor dysfunction, and epilepsy, primarily resulting from the lack of functional ubiquitin protein ligase E3A (UBE3A) protein expression in neurons. While current management remains largely symptomatic, the therapeutic landscape for AS is rapidly evolving. Emerging strategies aim to restore UBE3A function through upstream interventions, such as gene replacement therapy or unsilencing of the imprinted paternal allele, which is present but transcriptionally silenced in neurons due to genomic imprinting. This imprinting is mediated by the distal portion of a long non-coding RNA known as the UBE3A-antisense transcript (UBE3A-ATS). This UBE3A-ATS has become a key therapeutic target, with several approaches developed to unsilence the paternal allele, including antisense oligonucleotides (ASOs), CRISPR-based editing, synthetic microRNA, and other modalities. To date, three ASO programs have demonstrated promising signals in early clinical development, with reported improvements in clinical outcomes and electroencephalography (EEG) biomarkers. Given the potential for improved outcomes with early intervention, the inclusion of AS in broader genomic newborn screening programs is currently being explored. An early-intervention approach, or combination of approaches, holds significant promise for transforming the lives of individuals affected by AS with outcomes dependent on their age or genotype.
2026-03-22 | Emerging disease-modifying therapies for Angelman syndrome: A comprehensive review for pediatric neurologists.
Angelman syndrome (AS), a rare neurogenetic disorder affecting approximately 1 in 15,000 live births, results from loss of functional UBE3A gene expression and manifests with severe developmental delay, intellectual disability, absent speech, ataxia, epilepsy, and distinctive behavioral features. Until recently, only symptomatic management was available. This review provides pediatric neurologists with a comprehensive, practice-oriented overview of emerging disease-modifying therapies for AS, focusing on therapeutic approaches advancing through clinical development. The molecular pathophysiology of AS, natural history considerations critical for trial interpretation, and the current evidence for antisense oligonucleotide (ASO) therapies (ION582, GTX-102/apazunersen, rugonersen), gene replacement approaches (MVX-220), and next-generation strategies including CRISPR-based gene editing, artificial transcription factors, small molecules, and novel delivery platforms are reviewed. ASO therapies targeting the UBE3A antisense transcript represent the most clinically advanced approach, with three candidates showing proof-of-concept efficacy in Phase 1/2 studies and two advancing to pivotal Phase 3 trials. Gene replacement therapy offers potential single-administration treatment but faces challenges regarding safety, immune responses, and durability. Next-generation approaches including CRISPR activation, epigenetic editing, and blood-brain barrier-penetrating delivery systems show preclinical promise. Critical challenges include outcome measurement limitations, genotype stratification, long-term safety monitoring, and ensuring equitable access. These advances herald a transformation in AS clinical care and represent a milestone in precision pediatric neurology.
2026-03-01 | A xenotransplantation model for reactivation of paternal UBE3A using human-specific antisense oligonucleotides.
For many neurodevelopmental disorders, genetic treatment discovery is complicated by non-homology between human and non-human model system genomes. Antisense oligonucleotides (ASOs) influence protein expression by sequence-specific binding of RNA, resulting in targeted degradation or alternative splicing, and thereby provide a promising avenue for clinical therapeutics. Angelman Syndrome (AS), caused by loss-of-function of maternal UBE3A, has emerged as a monogenic neurodevelopmental disorder for which ASO therapy might be particularly amenable due to genomic imprinting. In an AS mouse model, Ube3a reactivation of the paternal allele using ASOs has been previously shown to rescue disease-relevant phenotypes. However, the poor sequence homology between murine and human UBE3A-ATS requires a human model system for screening of ASOs with clinical therapeutic potential. Here we evaluate an ASO targeting UBE3A-ATS using human induced pluripotent stem cell (hiPSC)-derived AS neurons in vitro and in vivo. We assessed the effect of ASO-treatment on cultured AS patient hiPSC-derived neurons through protein and RNA expression analysis. To increase clinical translatability, we designed a platform to evaluate this ASO in vivo by xenotransplantation of hiPSC-derived AS neurons into the brains of neonatal mice, with intracerebroventricular administration of the UBE3A-ATS ASO three weeks later. One week after ASO treatment, we observed in vivo reinstatement of UBE3A expression in xenotransplanted human neurons. These results highlight the potential for a versatile platform to evaluate efficacy of human-specific ASOs, for which AS provides an instructive proof-of-concept for therapeutic reactivation of UBE3A.
2026-02-03 | A dual-reporter mouse for therapeutic discovery in Angelman syndrome.
Angelman syndrome is a neurodevelopmental disorder caused by loss of the maternal UBE3A allele, the sole source of UBE3A in mature neurons owing to epigenetic silencing of the paternal allele. Although emerging therapies are being developed to restore UBE3A expression by activating the dormant paternal UBE3A allele, existing mouse models for such preclinical studies have limited throughput and utility, creating bottlenecks for both in vitro therapeutic screening and in vivo characterization. To address this, we developed the Ube3a-INSG dual-reporter knockin mouse, in which an IRES-Nanoluciferase-T2A-Sun1-sfGFP (INSG) cassette was inserted downstream of the endogenous Ube3a stop codon. The INSG model preserves UBE3A protein levels and function while enabling 2 complementary allele-specific readouts: Sun1-sfGFP and Nanoluciferase. We show that Sun1-sfGFP, a nuclear envelope-localized reporter, enables single-cell fluorescence analysis, whole-brain light-sheet imaging, and nuclear quantification by flow cytometry. Further, Nanoluciferase supports high-throughput luminescence assays for sensitive pharmacological profiling in cultured neurons and noninvasive in vivo bioluminescence imaging for pharmacodynamic assessment. By combining scalable screening, cellular analysis, and real-time in vivo monitoring in a single model, the Ube3a-INSG dual-reporter mouse provides a powerful platform to accelerate therapeutic development centered on UBE3A.
proteins
2026-09-29 | Phenotyping iPSC-derived neurons from Angelman patients and partial rescue via JNK pathway inactivation.
Angelman Syndrome (AS, MIM #105,830) is a rare neurodevelopmental disorder caused by imprinting defects, and it is marked by motor impairment, intellectual disability, speech limitations, and seizures. The condition arises due to the loss of function in neurons of the maternally-inherited UBE3A gene, mapping in the imprinted chromosomal region 15q11.2-q13, through a variety of genetic and epigenetic mechanisms. UBE3A encodes a ubiquitin E3 ligase, which is essential for synaptic plasticity. Most studies of AS have been performed on animal models, while induced pluripotent stem cells (IPSCs), mainly generated from patients with deletion, remain limited in number. Here we report on the generation and characterization of human cortical neurons derived from IPSCs obtained from children representative of the main AS genotypes: 3 with 15q11-13 deletion, 3 with UBE3A mutations, 3 with uniparental disomy, and 2 with imprinting defects. During early neuronal differentiation, morphological analyses highlighted a reduced dendritic branching and an increased number of thin filopodia, while migration assays revealed reduced neurite mobility in AS human neurons with the most severe genetic defect, namely the 15q11-13 deletion. At a later differentiation time point, electrophysiological analyses revealed impaired neuronal activity in AS patient-derived neurons. To investigate pathways potentially involved in synaptic dysfunction, we examined the JNK (c-Jun N-terminal kinase) signalling pathway, which plays key roles in neuroinflammation and synaptic development. We found increased JNK activation and, importantly, treatment with a JNK-inhibitor, D-JNKI1, partially rescued the neuronal morphological defects, significantly reducing the number of immature protrusions, as well as defects in electrophysiological properties. Our patient-specific models contribute elucidate how loss of UBE3A leads to aberrant neuronal maturation and function in the precocious stages of neuronal development and how treatment with D-JNKI1 may pave the way for new therapeutic possibilities.
2026-02-09 | Advances and challenges of precision epigenetic therapy in treating genomic imprinting diseases.
Genomic imprinting disorders (IDs) arise from the disruption of parent-of-origin-specific gene expression, a process governed by heritable epigenetic marks. Conventional therapies are largely symptomatic and fail to correct the underlying defect in dynamic gene regulation. Epigenome editing, using programmable DNA-targeting tools to rewrite epigenetic information, has emerged as a powerful therapeutic strategy that directly addresses this molecular pathology. This review synthesizes the transformative progress of the past decade, arguing that epigenome editing is poised to revolutionize the treatment of these conditions. We detail key breakthroughs in both editor design and in vivo delivery. These include the development of next-generation editors, such as compact "hit-and-run" systems that establish durable epigenetic memory after only transient expression-a critical feature for clinical safety. We then examine parallel advances in delivery platforms, including engineered adeno-associated virus (AAV) vectors with enhanced central nervous system (CNS) tropism and programmable lipid nanoparticles (LNPs) for precise extra-hepatic targeting. The therapeutic potential of combining these technologies is underscored by convincing preclinical data in models of Angelman (AS) and Prader-Willi syndromes (PWS), where the targeted rewriting of epigenetic marks has successfully reactivated silenced alleles and rescued disease-relevant phenotypes. Finally, we discuss the remaining challenges-including long-term durability and off-target safety-that must be overcome to translate this scientific potential into transformative medicines.
2025-09-16 | Structural analysis of HERC2/UBE3A and HERC2/DOCK10 complexes provides new insights into the molecular basis of Angelman, Angelman-like and Dup15q Syndromes
UBE3A and HERC2 are two mutually interacting HECT E3 Ubiquitin ligases whose genes are altered in 15q11.2-13.1 Duplication (Dup15q) Syndrome, Angelman Syndrome (AS) and other phenotypically-related mental retardation syndromes. Using quantitative binding assays, X-ray crystallography and sequence conservation analysis, we show that the HERC2/UBE3A complex occurs in probably most animals with a central nervous system, via a conserved interface involving the RLD2 domain of HERC2 and a "DxDKDxD" motif of UBE3A. We found that HERC2 also recognizes and binds to similar DxDKDxD motifs within a handful of other proteins relevant to brain development (DOCK10, PCM1, USP35, BAZ2B, ARID4A, ARIP4, RERE and MYT1). We further investigated the interaction of HERC2 with DOCK10, a RAC1- and CDC42-GEF protein that regulates dendritic spine morphogenesis in hippocampal neurons. Both disruption of the HERC2-binding motif in DOCK10 and knockdown of HERC2 affected the GEF activity of DOCK10. We also show that the DOCK10-induced dendritic spine formation is dependent on its ability to bind HERC2. Structural modeling of full-length DOCK10, free or bound to either RLD2, CDC42 or RAC1 indicates that the GEF activation of full-length DOCK10 requires a conformational change that is stimulated by binding to HERC2. Based on our data, we propose that under pathological conditions, in developing brains with an abnormal dosage of either HERC2 or its dominant partner UBE3A, increased or decreased amounts of HERC2/DOCK10 complexes could lead to altered GTPase activation. This in turn could affect dendritic spine formation and neurodevelopment.
2025-07-14 | A Human Angelman Syndrome Class II Pluripotent Stem Cell line with Fluorescent Paternal UBE3A Reporter
Abstract Introduction Angelman Syndrome (AS) is characterized in large part by the loss of functional UBE3A protein in mature neurons. A majority of AS etiologies is linked to deletion of the maternal copy of the UBE3A gene and epigenetic silencing of the paternal copy. A common therapeutic strategy is to unsilence the intact paternal copy thereby restoring UBE3A levels. Identifying novel therapies has been aided by a UBE3A-YFP reporter mouse model. This study presents an analogous fluorescent UBE3A reporter system in human cells. Methods Previously derived induced Pluripotent Stem Cells (iPSCs) with a Class II large deletion at the UBE3A locus are used in this study. mGL and eGFP are integrated downstream of the endogenous UBE3A using CRISPR/Cas9. These reporter iPSCs are differentiated into 2D and 3D neural cultures to monitor long-term neuronal maturation. Green fluorescence dynamics are analyzed by immunostaining and flow cytometry. Results The reporter is successfully integrated into the genome and reports paternal UBE3A expression. Fluorescence expression gradually reduces with UBE3A silencing in neurons as they mature. Expression patterns also reflect expected responses to molecules known to reactivate paternal UBE3A . Discussion This human-cell-based model can be used to screen novel therapeutic candidates, facilitate tracking of UBE3A expression in time and space, and study human-specific responses. However, its ability to restore UBE3A function cannot be studied using this model. Further research in human cells is needed to engineer systems with functional UBE3A to fully capture the therapeutic capabilities of novel candidates.
2025-03-18 | The gain-of-function UBE3AQ588E variant causes Angelman-like neurodevelopmental phenotypes in mice.
Mutations in the E3 ubiquitin ligase UBE3A that cause enzymatic gain-of-function result in disease phenotypes which differ from classic Angelman syndrome. However, these phenotypes are highly heterogeneous raising questions about the mechanistic basis of such phenotypic diversity. Here, we characterize a mouse model harboring a Ube3aQ606E gain of function variant (UBE3AQ588E in humans). Extensive behavioral phenotyping showed that animals possessing a maternally inherited mutation (Ube3amQ606E) paradoxically show many behavioral deficits indicative of overall UBE3A loss-of-function. These included pronounced motor deficits, hypoactivity, and reduced stereotypic behaviors. Moreover, brain weights and MRI analysis revealed global microcephaly with a postnatal onset, consistent with phenotypes described in Angelman syndrome model mice. Additional biochemical analyses demonstrated an increased abundance of UBE3A substrates in brain tissue and immunofluorescence analyses showed that microcephaly is not caused by increased apoptotic cell death. Together, our results strongly suggest a novel mechanism by which the Ube3amQ606E mutation leads to enhanced self-targeted degradation of UBE3A, leading to an overall loss of enzyme activity, resulting in Angelman-like phenotypes in vivo.
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2026-01-01 | Generation of human pineal gland organoids with melatonin production for disease modeling.
The pineal gland regulates circadian rhythms through melatonin production, yet human studies are limited by poor tissue access. To overcome this, we developed human pineal gland organoids (hPGOs) from pluripotent stem cells, modeling pineal development and function. Single-cell RNA sequencing revealed distinct mature and developing pinealocyte populations with transcriptomic profiles closely resembling the in vivo pineal gland. hPGOs produce melatonin, express adrenergic receptors, and respond to noradrenaline, mimicking physiological regulation. To model disease-related impairments, we generated hPGOs from Angelman syndrome (AS) patient-derived iPSCs, which exhibit disrupted pinealocyte differentiation and markedly reduced melatonin synthesis, reflecting AS-related developmental pathology. Additionally, transplanted hPGOs restored circulating melatonin in pinealectomized mice, demonstrating their potential for cell-therapy approaches. These findings establish hPGOs as a robust platform for probing pineal development, circadian regulation, and their disruption in neurodevelopmental and sleep-related disorders.
2025-12-18 | Extracellular vesicle dysfunction contributes to synaptic and cognitive deficits in a mouse model of Angelman syndrome.
Angelman syndrome (AS) is a devastating neurodevelopmental disorder caused by deficiency of the maternally inherited UBE3A. It is characterized by severe cognitive impairment, motor dysfunction, seizures, and developmental delays. Several mouse models of AS reproduce these debilitating features, including impaired memory function and synaptic plasticity, reduced dendritic spine density, and lysosomal alterations. Emerging research highlights the critical role of extracellular vesicles (EVs) in brain development and function, with growing evidence linking EV dysregulation to various neurological disorders. In this study, we first compared key features of EVs between wild-type (WT) and AS mice. EV secretion from forebrain synaptosomes was impaired in AS mice as compared to WT. Importantly, Ube3a was detected in EVs released from WT forebrain synaptosomes, suggesting a role for Ube3a in neuronal communication. We then identified TRPML1, a lysosomal ion channel, as a regulator of EV release and uptake, unveiling a novel molecular mechanism underlying EV dynamics. Furthermore, treatment with WT neuron-derived EVs significantly improved dendritic and spine morphology of cultured hippocampal neurons prepared from AS mice. Remarkably, systemic administration of WT brain-derived EVs restored hippocampal neuronal morphology and improved learning and memory in AS mice. These findings not only enhance our understanding of AS pathophysiology but also support EVs as a promising strategy for treating this currently incurable disorder.
2025-08-07 | Stem-cell modeling of cerebellar dysfunction of Angelman syndrome
Abstract Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function of the maternal allele of the neuron-specific imprinted gene UBE3A . Although AS presents with developmental delay, ataxia, epilepsy, and speech impairment, the distinct roles of various brain regions in its pathology remain unclear, hindering the design of effective therapeutic strategies. Of all brain regions, the nature and impact of dysfunction of the cerebellum in AS remain elusive. To start addressing this, we leveraged our optimized stem cell-based model of regionally patterned human cerebellar organoids (hCerOs) capable of producing major cerebellar neuronal subtypes, including Purkinje and granule cells, further matured in a two-dimensional (2D) culture system. We modeled AS using induced pluripotent stem cell (iPSC) lines carrying the common class II deletion and unaffected controls previously validated in our system. hCerOs from both backgrounds recapitulate lineage commitment and neuron-specific UBE3A imprinting. AS hCerOs consistently show reduced size, impaired neuroepithelial expansion, and diminished expression of glutamatergic and GABAergic progenitor markers. Transcriptomic profiling and functional assays assessing neuronal activity during the maturation stage uncovered delayed maturation, abnormal firing and increased neuronal excitability in AS cultures. These results position our hCerO model as a robust platform for future mechanistic studies and therapeutic screening aimed at targeting cerebellar dysfunction in AS.
2024-09-24 | Functional Recovery in Severe Genetic Syndromes: Clinical Experience of Cell Therapy in Angelman Syndrome
Genetic pathologies remain a major challenge in modern medicine, although medical technologies, laboratory diagnostics, and targeted therapy tools have significantly developed and expanded. Since etiopathogenetic therapy is not provided, children with genetic disorders receive only symptomatic treatment stabilizing their status and mitigating life-threatening factors, but not contributing to even a partially functional recovery of damaged organs. Angelman syndrome is a rare and severe genetic pathology characterized by delayed psychomotor development, seizures, and conduct disorders. Patients with this diagnosis have, in general, a poor prognosis for development and socialization. Stem cell transplantation is a promising approach to treating various genetic, neurodegenerative, and autoimmune diseases. The article describes two clinical cases of patients with verified Angelman syndrome who received a combination therapy with stem cell transplantation as a key method. Health outcomes were analyzed using the data of physical examination, assessment of neurological and psychological statuses, testing methods of neuroimaging and functional medicine, and laboratory testing of hormonal, mitochondrial, immune states of patients. The results showed a significant improvement in patients’ psychomotor development and a positive dynamic in laboratory and functional indicators. Therefore, the studied combination therapy approach could become a promising method for treating patients with severe genetic diseases accompanied by serious nervous system damage.
2023-12-15 | Exosomes from WT Mice Enhances Memory Recall-induced IEG Expression and Rescue Dendritic Spines Deficit in Angelman Syndrome Mice
Angelman syndrome (AS) is a rare neurogenetic disorder caused by deletion or mutations in the UBE3A gene, which lead to the deficiency of the UBE3A protein in neurons. UBE3A is crucial for normal neuronal communication, as it regulates the turnover of synaptic proteins and synaptic plasticity. Exosomes, small extracellular vesicles released by various cells, including neurons, play important roles in intercellular communication. Exosomes contain a variety of molecules, including proteins and nucleic acids, and can transfer these components between cells. Emerging evidence indicates that exosomes are critical for normal brain functions, and in recent years many studies have investigated the therapeutic potential of exosomes as vehicles for delivering therapeutic cargoes in various neurological disorders. In this study, we investigated the potential role of exosomes in regulating spine morphology in AS mice. Our results showed that activation of the lysosomal calcium channel TRPML1 stimulated exosome release from synaptosomes prepared from adult WT mice, but not from synaptosomes prepared from adult AS mice. Intriguingly, UBE3A was present in exosomes secreted from WT mice. It has been previously shown that hippocampal neurons of AS mice exhibit fewer dendritic spines, as compared to those from WT mice. Incubation of cultured hippocampal neurons from AS mice with conditioned medium from cultured hippocampal neurons from WT mice rescued the number of dendritic spines. Our data suggest that this effect is most likely due to exosomes in the medium, since purified exosomes from conditioned medium of WT neurons produced a similar rescue effect in cultured neurons from AS mice. Moreover, intravenous injection of exosomes prepared from synaptosomes of adult WT mice seemed to enhance contextual memory recall and associated immediate early gene (IEG) expression, and te number of dendritic spines in CA1 pyramidal neurons in adult AS mice. Whether and to what degree UBE3A present in WT exosomes participates in the rescue of AS neuronal morphology remains to be determined. Together, these results reveal both altered exosomal secretion and composition in AS mice. Treatment of AS neurons or adult AS mice with exosomes rescued dendritic spine deficits in vitro and in vivo. These results open new therapeutical approaches for using exosomes as a potential treatment for this disease.
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Drug Discovery Landscape
21 orphan drug designations for Angelman syndrome.
21 orphan drug designations for Angelman syndrome.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
non-replicating recombinant adeno-associated virus serotype hu68 (AAVhu68) vector, which expresses a variant of the UBE3A gene | gene therapies | FDA | MavriX Bio, LLC | |
insulin like growth factor 2 receptor ligand | small molecules | FDA | — | New York University |
14-species commensal bacterial flora with prebiotics and postbiotic complex composed of gut microbiome modulating formulation | other | FDA | — | Biom Pharmaceutical Corporation |
2'-O, 4'-C-Methylene-P-thio-adenylyl-(3'->5')-2'-O, 4'-C-methylene-P-thioguanylyl-(3'->5')-2'-O, 4'-C-methylene-P-thio-adenylyl-(3'->5')-2'-deoxy-P-thioadenylyl-(3'->5')-2'-deoxy-P-thio-thymidylyl-(3'->5')-2'-deoxy-P-thio-guanylyl-(3'->5')-2'-deoxy-P-thio-guanylyl-(3'->5')-2'-deoxy-P-thio-cytidylyl-(3'->5')-2'-deoxy-P-thio-adenylyl-(3'->5')-2'-deoxy-P-thio-cytidylyl-(3'->5')-2'-deoxy-Pthio-adenylyl-(3'->5')-2'-deoxy-P-thio-thymidylyl-(3'->5')-2'-deoxy-P-thio-cytidylyl-(3'->5')-2'-deoxy-P-thio-thymidylyl-(3'->5')-2'-O, 4'-C-methylene-5-methyl-P-thio-cytidylyl-(3'->5')-2'-O, 4'-C-methylene-5-methyl-P-thio-uridylyl-(3'->5')-2'-O, 4'-C-methylene-5-methyl-P-thio-uridylyl-(3'->5')-2'-O, 4'-C-methyleneguanosine | oligonucleotides | EMA | Ultragenyx Germany GmbH | |
2'-O-(2-methoxyethyl) modified antisense oligonucleotide targeting UBE3A antisense transcript RNA | oligonucleotides | EMA | Ionis Development (Ireland) Limited | |
2'-O-(2-methoxyethyl) modified antisense oligonucleotide targeting UBE3A antisense transcript RNA | oligonucleotides | FDA | Ionis Pharmaceuticals, Inc. | |
Cannabidiol | small molecules | FDA | — | Benuvia Operations LLC |
Adeno-associated virus serotype PTC3 expressing the human UBE3A gene | gene therapies | EMA | — | PTC Therapeutics International Limited |
Cannabidiol | small molecules | FDA | — | Biom Therapeutics |
Cyclo-L-glycyl-L-2-allylproline | small molecules | EMA | Orphix Consulting GmbH | |
Synthetic oligonucleotide selectively targeting UBE3A antisense RNA transcripts | oligonucleotides | EMA | Orphix Consulting GmbH | |
UBE3A antisense oligonucleotide with locked nucleic acids (UBE3A-ATS-LNA) | oligonucleotides | FDA | OHB Pediatrics Ltd. | |
Recombinant adeno-associated virus vector containing the active biological substance AAV-GTX-hUBE3A | gene therapies | FDA | — | PTC Therapeutics, Inc. |
cyclo(-L-Glycyl-L-2-Allylproline) | small molecules | FDA | Neuren Pharmaceuticals, Ltd. | |
Chimeric locked nucleic acid and ribonucleic-deoxyribonucleic antisense oligonucleotide specific for the human UBE3A-antisense transcript | oligonucleotides | FDA | Ultragenyx Pharmaceutical Inc. | |
Gaboxadol monohydrate | small molecules | EMA | Healx Technology Limited | |
[(4-benzylpiperazin-1-yl)(2-(isopentylamino)pyridin-3-yl)methanone]-phosphate | small molecules | FDA | — | Seneca Biopharma, Inc. |
antisense oligonucleotide specific to the antisense transcript of UBE3A | oligonucleotides | FDA | GeneTx Biotherapeutics, LLC | |
4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol | small molecules | FDA | Healx Limited | |
Recombinant adeno-associated viral vector serotype 9 carrying the gene for the human E6-AP ubiquitin protein ligase | gene therapies | EMA | — | PTC Therapeutics International Limited |
recombinant adeno-associated virus serotype 9 vector containing the transgene UBE3A encoding for ubiquitin protein ligase E3A/E6-AP | gene therapies | FDA | — | PTC Therapeutics, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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