(More update coming soon!)
Ben Philpot,Ph.D.
Kenan Distinguished Professor
Associate Director, UNC Neuroscience Center
Department of Cell Biology & Physiology University of North Carolina,Chapel Hill
Research and Lecture Content
Title：
“Translational opportunities for Angelman syndrome”.
Abstract：
“This talk will highlight the Philpot lab’s progress toward treating Angelman syndrome, highlighting two major therapeutic strategies: small molecule therapeutics and a gene therapy approach. For our small molecule therapeutics, we will discuss our lab’s efforts to develop drugs that can cross the blood-brain-barrier and unsilence the dormant paternal UBE3A allele. For our gene therapy approach, we will discuss our efforts to engineer a viral vector whose expression is meant to recapitulate the normal expression of UBE3A in the human brain. We will discuss these recent advances from our laboratory both in terms of their promise and their limitations, as well as our plan to overcome the limitations of the current approaches. Finally, we will discuss our efforts to develop tools to assess human gene-targeting therapeutics in a mouse model, as these efforts should improve the safety and efficacy of developing genetic treatments for Angelman syndrome, including ASOs and gene editing approaches.”
Ype Elgersma, Ph.D.
Professor of Molecular Neuroscience
Head of Research and Education, Dept. of Clinical Genetics
Scientific director ENCORE Expertise Centre for Neurodevelopmental Disorders
Erasmus MC, Rotterdam, The Netherlands
www.erasmusmc.nl/en/research/departments/clinical-genetics
Dr.Ype Elgersma’s research
Our laboratory investigates the molecular and cellular mechanisms that drive neurodevelopmental disorders, with the overarching goal of translating fundamental discoveries into therapeutic strategies. Our work is organized into three complementary research lines: advancing genetic diagnostics, elucidating disease mechanisms, and conducting translational studies aimed at improving patient quality of life. A major focus is Angelman syndrome (AS), a severe neurodevelopmental disorder caused by loss of function of the maternally inherited UBE3A gene. UBE3A encodes a ubiquitin ligase essential for protein turnover, yet its precise neuronal functions and the pathways disrupted by its absence remain poorly understood. To address this gap, we employ both animal models and in vitro systems to dissect UBE3A-dependent processes.
Despite limited mechanistic insight, therapeutic progress has accelerated through the development of antisense oligonucleotides (ASOs) that unsilence the normally imprinted paternal UBE3A allele. Several ASOs have now entered clinical trials, underscoring the urgency of answering key outstanding questions: the level of UBE3A required for functional rescue, the brain regions most critical for therapeutic targeting, and whether UBE3A reinstatement alone is sufficient in individuals with large chromosomal deletions affecting multiple genes. We are actively addressing these questions using established AS mouse models and newly generated lines, including AS deletion and AS-UPD/ICD models, to refine therapeutic strategies and deepen mechanistic understanding.
Kazuo Emoto, Ph.D.
Professor & Vice Dean,
Department of Biological Sciences, School of Science
PI & Deputy Director,
International Research Center for Neurointelligence (WPI-IRCN)
The University of Tokyo
Dr.Kazuo Enomoto’sresearch
Abstract：
Inactivation of the ubiquitin ligase Ube3a causes the developmental disorder Angelman syndrome, whereas increased Ube3a dosage is associated with autism spectrum disorders. Despite the enriched localization of Ube3a in the axon terminals including presynapses, little is known about the presynaptic function of Ube3a and mechanisms underlying its presynaptic localization. We found that developmental synapse elimination requires presynaptic Ube3a activity in Drosophila neurons. We further identified the domain of Ube3a that is required for its interaction with the kinesin motor. Angelman syndrome-associated missense mutations in the interaction domain attenuate presynaptic targeting of Ube3a and prevent synapse elimination. Conversely, increased Ube3a activity in presynapses leads to precocious synapse elimination and impairs synaptic transmission, suggesting pathogenic mechanisms associated with Ube3a dysregulation. We currently investigate detailed mechanisms of the Ube3a-kinesin interaction so I will discuss about how Ube3a protein is transported to synapses in control and pathological conditions.
Reference：
Furusawa K, Ishii K, Tsuji M, Tokumitsu N, Hasegawa E & Emoto K
Presynaptic UBE3A E3 ligase promotes synapse elimination by downregulation of BMP signaling.
Science 381: 1197-1205 (2023).
Shinji Saitoh,Ph.D.
Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
Dr.Shinji Saito’s research
Title：
Genotype-phenotype correlation over time in Angelman syndrome: Japanese experiences
Abstract：
Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function of maternal UBE3A. The major cause of AS is a maternal deletion in 15q11.2-q13 and the minor causes are a UBE3A mutation, uniparental disomy (UPD) and imprinting defect (ID). Previous reports suggest that all patients with AS exhibit developmental delay, movement or balance disorders, behavioral characteristics and speech impairment. In contrast, a substantial number of AS patients with a UBE3A mutation, UPD or ID were reported not to show these consistent features and to show age dependent change of their features. In this study, we investigated 134 patients with AS, including 57 patients with a UBE3A mutation and 48 patients with UPD or ID. Although developmental delay was present in all patients, 20% of patients with AS caused by UPD or ID did not exhibit movement or balance disorders. Differences were also seen in hypopigmentation and seizures, depending on the causes. Moreover, patients with a UBE3A mutation, UPD or ID tended to show fewer of the specific phenotypes depending on their age. Especially, in patients with UPD or ID, easily-provoked laughter and hyperactivity tended to become more pronounced as they aged. Therefore, the clinical features of AS based on cause and age should be understood and genetic testing should not be limited to patients with the typical clinical features of AS.
Evguenia Bekman,Ph.D.
Assistant Professor
Instituto Universitário Egas Moniz,
Monte da Caparica,Caparica,Portugal
Senior Researcher
Stem Cell Engineering Research Group
iBB-Institute for Bioengineering and Biosciences
Instituto Superior Técnico
Dr. Evguenia Bekman,Ph.D.’s research
Stem cell–based modeling of Angelman syndrome to investigate disease mechanisms and therapeutic strategies
João Camões dos Santos1,2, Francisca Cazaux Mateus1,2, Maria Arez1,2, Marta Cação1,2,3, Diana Carrasqueira1,2, Ândria Ferreira1,2, Simão Teixeira da Rocha1,2, Evguenia P. Bekman1,2,3
1iBB – Institute for Bioengineering and Biosciences and Department of Bioengineering, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal.
2Associate Laboratory i4HB Institute for Health and Bioeconomy, Instituto Superior Técnico, Universidade de Lisboa, Lisbon, Portugal.
3 Egas Moniz School of Health and Science, Campus Universitário – Quinta da Granja, Monte da Caparica, Caparica, Portugal
Abstract：
Angelman syndrome (AS) results from loss of neuronal UBE3A expression and is associated with significant cerebellar dysfunction. To establish human-relevant disease models, we generated a paired patient–parent induced pluripotent stem cell (iPSC) resource including megadeletion (MD) and paternal uniparental disomy (UPD) cases, within the Stem Cell Angel project funded by the Angelman Syndrome Alliance (ASA, 2022).
Using MD lines and matched controls, we implemented a cerebellar organoid model to characterize AS-related phenotypes in a three-dimensional context. Gene expression analyses indicate developmental dynamics consistent with the onset of UBE3A imprinting during organoid maturation. In parallel, high-density microelectrode array (MEA) recordings provide a functional framework to assess network-level properties in long-term cultures.
Building on this platform, the same MD lines are being used in complementary two-dimensional neuronal systems within the PineAS project, funded by Angelman e.V., to investigate the biological mechanisms underlying the activity of Pinus elliottii resin–derived compounds. Comprehensive chemical characterization of the resin revealed a unique and unexpected enantiomeric profile of its major terpenoid constituents, highlighting the potential importance of stereochemical composition for biological effects.
In 2D human neuronal cultures, we have established dosing parameters and viability windows for the resin and selected components, with no overt cytotoxicity observed under the tested conditions. Ongoing studies include transcriptomic profiling (RNA-seq), analysis of synaptic plasticity markers, MEA-based network assessments, and evaluation of cellular stress responses.
Together, this integrated strategy connects human cerebellar organoid disease modeling with mechanism-oriented intervention studies, providing a translational framework to investigate neuronal dysfunction and potential therapeutic avenues in Angelman syndrome.
Mark J. Zylka, Ph.D.
W.R. Kenan, Jr. Distinguished Professor
Director, UNC Neuroscience Center
The University of North Carolina at Chapel Hill
Dr.Mark Zylka’s research
Title:
Cas9 nickase gene therapy for Angelman syndrome
Abstract :
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 (in mice) or UBE3A-ATS (in humans). 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. We recently found that a Neisseria meningitidis nickase Cas9 variant (nNmCas9) 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 in AS model mice potently reduced Ube3a-ATS and elevated UBE3A protein levels throughout the cerebral cortex and hippocampus. This vector restored UBE3A expression in ~87% of cortical neurons, a higher efficiency than previously reported with active Cas9, dead Cas9, and zinc finger nuclease vectors. To advance for clinical application, we identified lead AAV-nNmCas9 vectors using a novel humanized UBE3A-ATS knockin mouse line. We will independently validate on-target activity of the lead vectors and evaluate potential off-target activities with human neurons containing the maternal 15q11-q13 deletion that causes AS. One lead vector will be advanced through investigational new drug (IND)-enabling studies to support therapeutic use in humans with AS. Collectively, our data indicate that nNmCas9 is a highly effective and likely safer genome editor for targeting human UBE3A-ATS in the treatment of AS.
Kiyoshi Egawa,Ph.D.
Hokkaido University Hospital. Department of Pediatrics, Lecturer
Dr.Kiyoshi Egawa’s research
Title:
Regional Imbalance of Tonic Inhibition Underlies Epileptic Features in a Mouse Model of Angelman Syndrome
Abstract :
Epilepsy and abnormal electroencephalography (EEG) rhythms are key features, but their mechanisms and treatment remain unclear. In a mouse model of Angelman syndrome, we investigated whether region-specific alterations in extrasynaptic GABA_A receptor–mediated tonic inhibition contribute to network dysfunction. Tonic inhibitory currents were recorded from principal neurons in the neocortex, hippocampus, and thalamus of maternal Ube3a knockout mice. Tonic inhibition was significantly reduced in layer 5 cortical and hippocampal CA1 pyramidal neurons, whereas it was preserved in thalamic relay neurons, indicating regional selectivity rather than a global deficit. The reduction in hippocampal tonic currents correlated with increased expression of the GABA transporter GAT1, suggesting enhanced GABA uptake as a potential mechanism.
To assess functional relevance, we examined the effects of pharmacological modulation of tonic inhibition. The α5-GABA_A receptor–selective positive allosteric modulator MP-III-022 attenuated abnormal slow-wave EEG activity, increased seizure thresholds in acute seizure paradigms, and improved anxiety-like behavior. In contrast, the δ-GABA_A receptor agonist gaboxadol enhanced slow-wave EEG activity and lowered seizure thresholds. These findings demonstrate that a region-specific imbalance of tonic inhibition contributes to EEG abnormalities and seizure susceptibility, support α5-GABA_A receptors as a potential therapeutic target for adjunctive treatment strategies. Although δ-subunit activation has been suggested to improve motor function in Angelman syndrome models, our results indicate that, depending on dosage, δ-subunit activators may carry a risk of exacerbating EEG abnormalities and seizure susceptibility as potential adverse effects.
Carmen DeCaro, Ph.D.
Department of Pharmacy, University of Naples “Federico II”, Naples, Italy
Dr.Carmen DeCaro’s Research
(＋Prof. Edoardo Ferlazzo)
Title:
Role of gut microbiota as biomarker in Angelman Syndrome (AS)
Abstract :
Over the last two decades, increasing attention has been given to the role of intestinal microbiota in central nervous system (CNS) disorders and to the microbiota–gut–brain axis (MGBA) as a potential therapeutic target. Several epilepsy syndromes are characterized by neuroinflammation, alterations in neuronal pathways and neurotransmitters, and gut dysbiosis, as shown in both animal models and human studies. One major limitation of gut microbiota (GM) research is the high variability among samples; therefore, studies focusing on specific populations, such as rare epilepsy syndromes, are strongly encouraged. To date, no studies have investigated GM composition in patients with AS. The objective of this project was to characterize the intestinal microbiota composition and quantified the short chain fatty acid (SCFAs) in AS patients to improve the understanding of this syndrome and identify potential biomarkers and therapeutic targets through fecal samples in the stool. In this multicenter study, we recruited patients with confirmed AS diagnosis and age-matched healthy volunteers. Controls were selected among relatives of AS patients to reduce dietary differences. Stool samples were collected from each participant and analyzed using the 16S Metagenomic Sequencing Library Protocol for the Illumina MiSeq System. The results showed some difference in intestinal microbiota composition between AS patients and controls. These findings suggest that gut microbiota may represent a potential therapeutic target in Angelman syndrome.
Prof. Edoardo Ferlazzo M.D.-Ph.D.
Full Professor of Neurology- University Magna Graecia of Catanzaro, Catanzaro, Italy