Testing the efficacy of antisense oligonucleotides (ASOs) against UBE3A-ATS in human neurons

Stormy Chamberlain, Ph.D. – University of Connecticut Health Center
$200,000 (2 years)

This research study builds upon previous ASF-funded research conducted by Dr. Art Beaudet at Baylor College of Medicine and will determine whether a drug that increases UBE3A expression can restore normal function to human AS brain cells. The study will also help identify potential biomarkers that can be used in the lab or in clinical trials to determine whether drugs that unsilence UBE3A are restoring proper function to the brain cells. Finally, the research will generate genetically identical pairs of AS and control human stem cell lines that can be used by other researchers to study AS.

Previous research at this institution generated patient-specific stem cells from AS patients with mutations in the UBE3A gene. The researchers plan to use genome editing tools to correct the mutation in AS stem cells to produce cells that are genetically identical to the AS patient, but do not have AS. They will then convert the AS and corrected stem cells into brain cells and use whole genome RNA sequencing to identify the differences between AS and typically developing brain cells. Once they have identified differences, they will treat the AS brain cells with a drug that unsilences paternal UBE3A to determine whether the drug restores proper function to AS brain cells.



An effectiveness trial: Speech generating devices in children with Angelman syndrome

Anjali Sadhwani, Ph.D. – Boston Children’s Hospital
$198,948  (2 years)

The overarching goal of this research is to generate evidence to guide families on the appropriate selection and use of speech generating devices (SGDs) that may help individuals with AS better communicate. The researchers will conduct a trial of individuals with AS aged 7-15 years who use presymbolic means of communicating and live within a 60-mile radius of Boston, MA. First, the research team will use feature matching—a comprehensive evaluation of sensory and communications needs—to match the individual to the best speech generating device based on his or her specific needs. Then, the team will implement a training program to teach the participant how to use the device to make a request (i.e., request their preferred object). This focus allows the research team to determine whether the training program is effective, and produces consistent results across all participants and devices that may be applicable to help families in the real-life setting in the future.



Validation of alpha1-NaKA inhibition as a novel therapeutic strategy for the mouse model of Angelman syndrome

Hanoch Kaphzan, Ph.D. – University of Haifa, Israel
$200,000 (2 years)

At approximately two weeks of age in a proven AS mouse model, there is an increase in the expression and subsequent activity of a specific molecule prior to other molecules in the AS brain, which results in deficits in the part of the brain that controls learning and memory. Interestingly, the increased expression or activity of that particular molecule was reported in other autistic spectrum disorders as well. This research project seeks to determine if a specific drug that reduces the activity of that specific molecule will rescue the cognitive phenotype and decrease the deficits in learning and memory. In doing so, the research team will be able to answer questions for future research about why the increased activity of that molecule creates AS symptoms, and why decreasing the activity reverses AS symptoms. This research will help the AS research community determine the best medications to help improve learning and memory.



Identification and characterization of novel targets and activators of E6AP

Ben Distel, Ph.D. – Academic Medical Center, Amsterdam, Netherlands
$199,705  (2 years)

This research project aims to identify and characterize proteins in the brain that are affected by the absence of UBE3A. These proteins serve an unknown purpose in brain development. This research will help provide insight into how AS symptoms develop by determining how these proteins’ functions are impacted by the absence of UBE3A. The research team will also explore ways to enhance UBE3A activity. This may help to boost the activity of the dormant, paternal copy of UBE3A and reduce AS symptoms.



Validation of biomarkers for Angelman syndrome clinical trials

Ben Philpot, Ph.D. – University of North Carolina-Chapel Hill  |  Heather Hazlett, Ph.D. – Carolina Institute of Developmental Disabilities at University of North Carolina-Chapel Hill  |  Ron Thibert, M.D. – Massachusetts General Hospital
$295,970 (2 years)

This unique research project is the AS research community’s first attempt at establishing biomarkers as benchmarks for success in future AS clinical trials. The research team’s approach leverages what has been learned from the two ASF-funded Angelman Syndrome Clinics and the advancements in AS mouse models, taking advantage of both to measure traits in individuals with AS that could be used to prove the effectiveness of clinical trials. The research team will identify biological characteristics that may indicate if individuals are positive responders to treatments, which can be used in all AS clinical trials in the future. The research team will evaluate three areas to establish benchmarks to indicate future clinical trial success:

  1. Brain circuitry in AS patients using MRI
  2. Brain electrical activity through EEGs
  3. Deficits in peripheral nerve functions, not just central nerve functions