Defining Treatment Parameters for Angelman Syndrome

Ben Philpot, Ph.D. – University of North Carolina – Chapel Hill  / Ype Elgersma, Ph.D. – Erasmus Medical Center, Rotterdam, Netherlands
$400,000 (2 years – $200,000 per institute)

A previously developed mouse model for Angelman syndrome (AS) enables the maternal copy of the Ube3a gene to be turned on and off.  By activating the Ube3a gene at different stages of the mice’ lives, it will help the research community define the optimal age window for AS treatment.  The team will also research how broadly the gene needs to be turned on in specific regions of the brain to affect treatment.  Investigators will determine whether AS therapeutics need to be maintained throughout life, or if AS only needs to be treated during early life.

Ube3a-ATS Targeted Antisense Oligonucleotides As Therapies for Angelman Syndrome

Arthur Beaudet, M.D.  / Linyan Meng, Ph.D. – Baylor College of Medicine, Houston, TX
$200,000 (2 years)

Oligonucleotides are short, single-stranded DNA or RNA molecules.  Previous studies have demonstrated that the antisense RNA of Ube3a (Ube3a-ATS) silences the paternal Ube3a gene.  The investigators propose using antisense oligonucleotides (ASOs) to specifically target Ube3a-ATS, which is anticipated to unsilence the paternal Ube3a gene.  Additionally, the researchers hope to determine the optimal treatment window, or age by which treatment should be administered, using a mouse model that is engineered to have a human-like Ube3a gene region.  They will try this in young and adult ages and use behavioral parameters as measurements of effectiveness.  The team will screen for antisense oligonucleotides that work in humans by studying their activity in a mouse model engineered to have a human-like Ube3a gene region.  Overall, these studies will help to determine whether antisense oligonucleotides are a viable approach to the development of a treatment for Angelman syndrome.

Identification and Manipulation of the Phosphatases that Produce Aberrant Phosphorylation of CaMKII in Angelman Syndrome

John Lisman, Ph.D. – Brandeis University, Boston, MA
$200,000 (2 years)

Previous work on a major synaptic protein, Calcium/calmodulin-dependent protein Kinase II (CaMKII), suggests that it has a central role in producing the developmental deficits in Angelman syndrome (AS).  This research seeks to better understand how CaMKII activity is mediated by a group of regulatory proteins known as phosphatases.  AS treatment strategies involving CaMKII activation via phosphatase-catalyzed dephosphorylation may result from such studies.

Investigating the Causal Role of Arc in Angelman Syndrome Pathogenesis

Jason Shepherd, Ph.D. – University of Utah, Salt Lake City, UT
$170,202 (2 years)

Previous research discoveries have indicated that one of the UBE3A target proteins, Arc (activity-regulated cytoskeleton-associated protein) plays a critical role in regulating synaptic plasticity and long-term information storage in the brain.  By understanding how Arc is involved in learning and memory in the context of Angelman syndrome (AS) and how it is regulated in the Arc-dependent process, this research has the possibility to lead to development of approaches for therapeutic interventions that target the learning and memory deficits in AS.

Preclinical Validation of Behavioral, Molecular, and Electrophysiological Effects of Acamprosate in a Mouse Model of Angelman Syndrome

Craig Erickson, M.D. – Cincinnati Children’s Hospital Medical Center

The principal objective of these studies is to determine if acamprosate, a drug that is approved by the Food and Drug Administration for the treatment of alcoholism in adults and works to correct imbalances in excitatory and inhibitory signaling in the brain, is a viable treatment option in Angelman syndrome (AS).  Acamprosate will be rigorously tested in the AS mouse for improved brain signaling, as well as in several behavioral tests for learning, memory and motor functioning compared to typical mice.  Validation in the mouse model may lead to expedited clinical trials in individuals with AS.

Studies to Determine How Angelman Syndrome-associated Missense Mutations Disrupt UBE3A Function

Mark Zylka, Ph.D. – University of North Carolina – Chapel Hill, NC
$200,000 (2 years)

Angelman syndrome (AS) is typically caused by genomic deletions that encompass the maternal copy of UBE3A.  In some patients with AS, the UBE3A protein is present but with a single amino acid change known as a missense mutation.  Investigators noticed that essentially all of the AS-associated missense mutations are located in specific regions (or “hot-spots”) of the UBE3A protein that are critical for UBE3A function.  This research will evaluate how each known mutation affects UBE3A function.  Furthermore, it has the potential to more accurately predict whether new mutations in UBE3A are benign or cause AS.  Such studies could lead to therapeutics that stabilize UBE3A in a subset of patients with AS.