Novel therapeutics for Angelman syndrome by manipulating Ube3a expression

Benjamin Philpot, PhD – University of North Carolina Chapel Hill
$199,972 (2-year award)

Funding for this grant is an attempt to promote research targeted to identifying agents or druggable compounds that may increase expression of UBE3A in brain neurons. Using multidisciplinary facilities, advanced genetic engineering and robotic drug analysis, this grant attempts to screen thousands of chemicals and compounds through an experimental protocol that will enable identification of UBE3A protein expression. This research has exciting promise of identifying potential new therapeutic agents or identifying new protein or molecular pathways that may improve UBE3A expression.

Rescue of Angelman Syndrome Learning Deficits by an Investigational New Drug

John Marshall, PhD – Brown University, Providence, RI
$198,899 (2-year award)

As research improves our understanding of synapse function in normal individuals and how it is abnormal in those with AS, we are approaching an exciting time when therapeutic drug agents or chemicals can be tested in the AS mouse model. Accordingly, this grant funds an investigator who has experience in developing synaptic-related compounds that are active in improving synaptic function with the aim of improving cognitive function. Funding for this project is consistent with other efforts by ASF to explore novel avenues of drug treatment that may ameliorate or potentially cure the symptoms of AS.

NRB-a/ErbB4 and Dopamine D4 Receptors as Therapeutic Targets to Treat Cognitive Deficits in Angelman Syndrome

Eric Klann, PhD – New York University
$197,580 (2-year award)

This project enabled Dr. Klann to continue his studies on the synapse and on the action of an important group of proteins, the neuregulins. At the neuronal cell membrane, these proteins are known to interact with an important receptor (ErbB4) that can initiate crucial intracellular signaling. Studies in Angelman mice by Dr. Klann have demonstrated that one of the neuregulins, neuregulin-1, appears to be increased in mouse neurons. His lab is attempting to block the actions of this specific receptor pathway and then measure to what extent this inhibition might rescue or repair some of the behavioral and/or synapse problems of AS.

Identification of UBE3A Ligase Substrates

Peter Howley, MD – Harvard Medical School
$200,000 (2-year award)

Dr. Peter Howley, a long-time investigator into the role of UBE3A, has been funded by ASF to conduct state-of-the-art studies that have promise for identifying new protein targets and interacting proteins for UBE3A. This work involves using a newly established method for identifying targets (compPASS) that uses catalytically inactive forms of UBE3A proteins to identify binding and interactions with other proteins in the cell. The expectation is that this new approach will soon lead to the identification of new UBE3A protein targets, providing additional possibilities for new therapeutic strategies in AS.

Novel Ube3a Isoform and Angelman Syndrome

Yong-Jui Jiang, MD, PhD – Duke University, Durham, NC

At the DNA level, UBE3A represents a single region of DNA molecules but when UBE3A makes its proteins multiple different proteins appear and these are termed isoforms. In this project, Dr. Jiang is evaluating some of the shorter protein isoforms that have previously been less studied than the longer ones. It is hoped that an analysis of these isoforms in the AS mouse model will lead to additional understanding about the repertoire of cellular mechanisms that UBE3A can direct.

Determining the Role of the E6-AP Isoforms in Synaptic Maturation

Scott Dindot, PhD – Texas A&M University, College Station, TX

This project funds work on a special type of mouse model in which production of the UBE3A protein can be identified by use of a yellow fluorescent tag. This then enables the tracking and localizing of certain UBE3A proteins within Angelman mice neurons. UBE3A produces several types of proteins, called isoforms, and Dr. Dindot’s lab has identified how specific isoforms localize in the nucleus, cytoplasm or in the synapse region. This research is important in understanding where UBE3A proteins operate in all compartments of the cell and it helps define areas for protein interactions which may lead to development of new therapeutic strategies.

2009 Behavioral Research Awards

Use of Conventional and Complementary and Alternative Treatments for Problem Behaviors in Angelman Syndrome

Dr. Sarika Peters – Vanderbilt University

Due to the relative rarity of AS, best treatment practices are often derived from parent questionnaires sent throughout the U.S. With this in mind, the ASF funded this research work by Dr. Peters to use a web-based parent questionnaire aimed at delineating extensive information regarding the use of traditional and alternative treatments for challenging behaviors in AS. The work showed that more than half (53% of 333 parents completing the survey of the caregivers) reported individuals using at least one alternative treatment. The most popular alternative treatments include melatonin, omega-3 fatty acids/fish oil, folic acid and magnesium. Data from this questionnaire are still under evaluation.

Evaluation of a Standard Behavioral Protocol in the Treatment of Sleep Problems in Young Children with Angelman Syndrome

Dr. Keith Allen – University of Nebraska Medical Center

Sleep disorders are well-known problems in AS. ASF has been interested in funding projects which develop intervention strategies and extend the knowledge gained from previous work done on sleep disorders in AS. With this in mind, this project studies families of older children with AS who have sleep disorders. It provides in-home and clinic assessments in an attempt to help delineate successful practices for treatment of sleeping problems.