Every summer, the world’s top researchers in AS come together at the ASF Research Symposium to discuss the latest in AS cutting-edge research.
Below, is a synopsis of the scientific presentations from the 2017 ASF Research Symposium developed by Dr. Stormy Chamberlain, ASF’s Scientific Advisory Committee chair.
Overview of AS research landscape
Ben Philpot, Ph.D., University of North Carolina
Becky Burdine, Ph.D., Princeton University
Drs. Philpot and Burdine summarized research efforts to frame the symposium. They briefly discussed efforts to identify UBE3A substrates, two of the major therapeutic approaches—gene therapy and unsilencing of the paternal copy of UBE3A, phenotype-specific treatments (i.e., seizure, anxiety, sleep approaches), and biomarkers. Biomarkers are features that can be objectively measured to determine whether a treatment is working. Finally, unanswered research questions and challenges facing the development of therapeutics were discussed.
UBE3A isoform localization and function
Ype Elgersma, Ph.D., Erasmus University Medical Center, Rotterdam, Netherlands
A keynote talk by Dr. Elgersma reported on his ongoing work using a clever ASF-funded mouse model to determine whether UBE3A is required throughout life, or whether it is only necessary for a defined window during development. He also reported preliminary results regarding the locations in the cell of the three UBE3A isoforms and how much of the total UBE3A protein each isoform comprises. This work on the isoforms was also a project funded by ASF.
Deciphering the role of CAMK2A in Angelman syndrome mice
Geeske van Woerden, Ph.D., Erasmus University Medical Center, Rotterdam, Netherlands
Dr. van Woerden discussed her ongoing work to understand the relationship between CamKII phosphorylation and Angelman syndrome. Specifically, she is determining whether CamKII dysfunction in humans can cause AS-like phenotypes. In the second part of her talk, she discussed her ASF-funded efforts to explore cognitive tests in AS the mouse model.
Arc-dependent homeostatic synaptic plasticity is altered in Angelman syndrome model mice
Jason Shepherd, Ph.D., University of Utah
Dr. Shepherd discussed work showing that ARC and UBE3A do not physically interact as some reports had suggested. However, he found that ARC protein is still misregulated in AS mouse neurons. Dr. Shepherd reported data exploring how ARC becomes misregulated and how this misregulation leads to defects in homeostatic synaptic plasticity, the process by which neurons regulate their own excitability relative to the activity around them. This ASF-funded work was recently published in Frontiers in Molecular Neuroscience.
Gene therapy for central nervous system diseases
Steven Gray, Ph.D., University of North Carolina
An exciting talk by Dr. Gray introduced us to the current research landscape of AAV-mediated gene therapy for disorders of the CNS. He presented important data showing how AAV gets distributed throughout the brain during a therapeutic infusion: how many cells and how far it spreads throughout the brain depending on how it is delivered. He discussed some of the honest drawbacks of AAV-mediated gene therapy, but also discussed his recent successful treatment of giant axonal neuropathy using this type of gene therapy, which was a first-in-human trial of gene therapy for a brain disorder. Stay tuned for an exciting announcement from ASF regarding gene therapy.
Disrupted synaptic transmission and protein homeostasis in an Angelman syndrome mouse model
Shengfeng Qiu, Ph.D., University of Arizona College of Medicine
Dr. Qiu presented his work delving deeply into the function of specific neurons in the AS mouse brain, especially the prefrontal cortex. His preliminary data suggest altered neuronal connectivity (i.e. synapses) that is dependent on developmental stage and/or age. In addition, his data suggest that autophagy, a process by which cells dispose of proteins, may be impaired in AS mouse neurons. He hypothesizes that enhancing neuronal autophagy may correct some issues in the AS brain.
MRI and DTI in children with Angelman syndrome reveals white matter pathology linked to motor deficits
Mark Shen, Ph.D., University of North Carolina
Dr. Shen gave a riveting talk reporting deficits in the white matter of children with AS. This ASF-funded study, involving children 3-10 years old, was carried out at the ASF-funded Angelman Syndrome Clinic at UNC-Chapel Hill. Decreased white matter volume and compromised white matter integrity were seen. These findings were specific to AS, and not seen in kids with autism or Fragile X syndrome. Mark also showed some of the recently published data from the Philpot lab reporting similar findings in AS mice. AS mice have decreased brain volume and white matter. The parallel white matter changes seen in both humans and mice may be an important biomarker to inform how well therapies may be working. Although structural changes in white matter seems like a bad thing, it is so important to have this specific biomarker in order to see whether therapies might be working.
BDNF-enhancer drug facilitates learning in Angelman mice
John Marshall, Ph.D., Brown University
Dr. Marshall discussed his ongoing work with CN2097, a compound that restores the disrupted BDNF signaling in AS mice. The mechanism of how this works was investigated. This work has implications for learning and memory in AS, and may suggest a novel therapeutic approach.
Clinical trials for targeted treatments in neurodevelopmental disorders: Past experience and new directions
Elizabeth Berry-Kravis, M.D., Ph.D., Rush University Medical Center
A keynote talk by Dr. Berry-Kravis ended the Tuesday talks. Dr. Berry-Kravis has been involved in various clinical trials to test therapeutics for Fragile-X syndrome. She discussed the design, outcomes, and lessons learned from each of these approaches, as well as shared her experience interacting with the FDA. She made important points about placebo effects, establishing outcome measures to assess improvements in key domains expected to be impacted by the therapy, clinical trial design–including models for evaluating a therapeutic effect on learning, potential need to stratify patients based on age or severity to see significant efficacy of a therapeutic, and need to find ways to test young children with developmental disorders before determining if a targeted therapeutic has benefit.
Eye gaze and pupillary response in Angelman syndrome
Logan Wink, M.D., Ph.D., Cincinnati Children’s Hospital Medical Center
Dr. Wink spoke about her preliminary data using eye gaze and pupillary response as a read-out in individuals with AS. These measures are objective ways to measure an individual’s response to stimulus, however, some features of AS may make these measurements difficult. Dr. Wink reported that 47% of individuals with AS (8 of 17) completed the eye tracking task, which sought to determine whether individuals with AS preferred a social scene versus a geometric scene. This task has been previously used to determine social preference in autism spectrum disorders.
Understanding healthcare utilization among patients with Angelman syndrome: Results from the AS natural history study
Raquel Cabo, Ovid Pharmaceuticals
Lynne Bird, M.D., University of California, San Diego
Ms. Cabo and Dr. Bird presented data mined from the natural history study to determine the Health Resources Usage (HRU) and Medical Services Usage (MSU) by individuals with AS. Data collected from 302 individuals with AS revealed the frequency of hospitalization, surgery and medication, as well as the usage of early childhood intervention and specific therapies (PT, OT, ST) amongst individuals with AS. Patients with deletions had significantly more seizure-related hospitalizations, and used more prescription medications. Sleep, seizures and gastrointestinal problems were the main reasons for prescription and over-the-counter medication use.
Developmental Milestones in children with Angelman syndrome—findings from the AS natural history study
Anjali Sadhwani, Ph.D., Boston Children’s Hospital
Dr. Sadhwani presented similar data from the Natural History Study regarding developmental milestones to determine the ages at which participants achieved motor and language skills. The attainment of specific skills was determined across different genetic etiologies (deletion, UBE3A mutation, UPD, or ICD).
Delta rhythmicity is a reliable EEG biomarker in Angelman syndrome
Mike Sidorov, Ph.D., University of North Carolina
An interesting talk by Dr. Sidorov discussed collaborative efforts from the Philpot group, Dr. Ron Thibert, and Dr. Lynne Bird reporting the quantification of EEG signatures for use as a biomarker for AS. Specifically, the group quantified delta power and dynamics in individuals with AS as well as the mouse model. They found that delta power is significantly increased in both humans and mice lacking UBE3A. Furthermore, they developed a computational tool, called PARADE, which automates the quantification of EEG signatures in both species. This ASF-funded work, which suggests a useful and robust biomarker for anticipated clinical trials, was recently published in Journal of Neurodevelopmental Disorders.
Anxiety in individuals with Angelman syndrome
Anne Wheeler, Ph.D., University of North Carolina
Dr. Wheeler described her work in the ASF-funded AS clinic at UNC where she is studying anxiety in individuals with AS. Anxiety seems to be a significant issue for many individuals with AS, as evidenced by Anne’s study as well as robust attendance at talks addressing anxiety during the ASF Family Conference.
AAV-mediated strategies for the treatment of Angelman syndrome
Jodi Cook, Ph.D, Agilis Biotherapeutics
Edwin Weeber, Ph.D, University of South Florida
Dr. Cook updated the group on their progress to develop an AAV-based gene therapy for AS. Agilis licensed an AAV therapeutic for AADC-Deficiency from an academic lab in Taiwan that has data on 23 treated subjects. Jodi presented their positive results, supporting the gene therapy approach. Dr. Weeber from the University of South Florida continued and described the preclinical studies being performed using AAV to deliver UBE3A as a gene replacement in the AS mouse model. Positive results for rescue of the synaptic plasticity and memory defects were described using a human UBE3A gene. In addition, a brief description was provided for a novel gene deletion rat model for AS undergoing initial characterization.
Mapping UBE3A effects on sociability to a subcellular compartment, autism protein interaction network, and circuit.
Matthew Anderson, M.D., Ph.D., Harvard Medical School
A talk by Dr. Anderson summarized data from his recent publication describing sociability in AS mice and mice with two extra copies of Ube3a. In brief, he found that AS mice have increased social interactions and Ube3a overexpressing mice had decreased social interactions. His studies suggest that this may be mediated through the Cbln1 gene in mice. This work has been published in Nature.
EEG as a biomarker to assess the efficacy of therapeutics in Angelman syndrome
Anne Anderson, M.D., Ph.D., Baylor College of Medicine
Dr. Anderson analyzed EEG data from individuals with AS who were enrolled in the minocycline clinical trial. She described the difficulty in reading the EEG data from the study due to differences in the program that stores EEG data. However, upon successfully reading and quantifying these EEGs, she was able to see reduction of delta power, which is an improvement in AS individuals 8 weeks after they stopped minocycline. It is not clear whether this reflects an improvement due to minocycline or a response to removal of the drug. Minocycline is currently not recommended for use to treat AS.
Rescue of hippocampus-dependent behaviors and physiology in a mouse model of Angelman syndrome by deletion of the Ephexin5 gene.
Ms. Gabrielle Sell, B.S., Johns Hopkins University
An interesting talk by Ms. Sell, a graduate student in Dr. Seth Margolis’ lab discussed their recent work with Ephexin 5 (E5). Dr. Margolis’ lab had previously shown that E5 is a target for UBE3A. It is increased in AS and may contribute to changes in dendritic spines in the hippocampus. Gabrielle mated E5 knockout mice with AS mice to see if reduction of E5 could rescue some features of AS mice. She found that E5 reduction did not rescue all phenotypes in AS mice, but that certain hippocampal-specific behavioral, cell biological, and electrophysiological phenotypes were, in fact, rescued. This data makes Ephexin5 an interesting potential therapeutic target for learning and memory phenotypes.
Establishing a molecular phenotype for Angelman syndrome induced pluripotent stem cell-derived neurons
Ms. Carissa Sirois, M.S., University of Connecticut School of Medicine
Ms. Sirois, a graduate student in Stormy Chamberlain’s lab discussed how she used CRISPR to correct an AS-causing mutation in UBE3A in human stem cells. She turned these cells—identical twins with and without AS—into neurons and asked whether the AS cells had physiological changes. She also compared gene expression genome-wide between AS and typical neurons and identified differences. She is using these approaches to determine if ASOs can restore AS phenotypes in human neurons and to determine how different UBE3A isoforms function.