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Angelman Syndrome Research Summaries

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Research Summaries

Year of Publication:

1996 | 1997 | 1998 | 1999 | 2000 | 2002 | 2003 | 2005 | 2006 | 2007 | 2008 | 2009

1996

Joseph Wagstaff
Melatonin and Sleep in Angelman Syndrome

This research grant determined if melatonin, a well-known drug that has been used to improve sleep, could be effective in individuals with Angelman syndrome (AS). Children with AS were monitored at night using motion detecting devices and sleep observations. This study showed positive results and its findings helped lead to the established therapeutic use of melatonin to help improve sleep in AS.
Amount Funded: $10,000
Institution: Boston Children's Hospital

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1997

Richard Olsen
GABA beta3 Deficient Mice

The gene that is defective in AS is UBE3A and in 70% of individuals who have AS this gene and genes nearby it are deleted from chromosome 15. This project sought to determine if one of the adjacent genes to UBE3A was important in causing abnormalities when it was also deleted in combination with UBE3A. The experimental approach used mice that were only missing the adjacent gene, GABRB3, but had UBE3A in place and not deleted. The results of this study as well as future studies on this question showed that UBE3A is the major gene that when disrupted causes the seizures in AS.

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1998

Nicolay Walz
Behavioral Aspects of Angelman Syndrome

This research project was one of the earliest extensive surveys of behavioral traits in AS and was funded and enabled by the Angelman Syndrome Foundation (ASF) because of ASF’s affiliation with so many families within and outside of the United States. Data from this questionnaire, and further follow-up studies by the investigator, subsequently led to several crucial papers. These publications showed that individuals with AS have abnormalities in sensory processing and therapeutic intervention was discussed.
Amount Funded: $3,213
Institution: Cincinnati Children's Hospital

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1999

Stephen Calculator
Use of Enhanced Natural Gestures and Angelman Syndrome

Individuals with AS are quite animated in their attempts at communication and can be pro-social even though they have severe speech impairment. Although fluent sign language is beyond the motor and cognitive abilities of those with AS, there is an important type of gesturing communication that occurs by more simplistic physical signals that are less complicated than formal sign language. The purpose of this funded project was to gain information about how to use, and build upon, the natural gesturing capabilities of those with AS.
Amount Funded: $10,581
Institution: University of New Hampshire

Richard Olsen; Tim DeLorey
GABA-A receptor beta 3 submit knockout mice

In some individuals with AS, severe seizure problems can limit developmental outcomes and disrupt family life. Those with the most severe seizures in AS have a large chromosomal deletion which removes or disrupts UBE3A but the deletion also removes an adjacent gene, GABRB3, important in regulating the membrane sensitivity of the neuron. It was hoped that developing a mouse model with GABRB3 deleted would provide more information about epilepsy and EEG patterns in AS. This work as well, as prior work funded in 1997, helped clarify the primary and major role of UBE3A disruption in causing seizures in AS.

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2000

Louis Tiranoff and Jill Clayton-Smith
(1) History & Discovery: Dr. Harry Angelman's Observations, (2) Special Issues of Adolescence and The Transition to Adulthood

Visual media plays a powerful role in helping families and others understand the natural history and many of the day-to-day concerns that parents have for their children and adults with AS. This work combines the skills of individuals experienced with the behavioral and clinical problems of AS with the talents of someone able to produce audiovisual and other types of transferable media. This project developed DVDs and other communication formats to enable others to actually see children and adults with AS in many different home and living situations.

Nicolay Walz
Sleep Patterns and Autistic Symptomology in Angelman Syndrome: Further Delineation of the Behavioral Phenotype

ASF maintains contact with hundreds of families throughout the United States and in other parts of the world and this contact serves as a valuable resource for investigators wishing to learn more about certain behavioral or medical problems of those with AS. In this project, information was gleaned from over 300 families who provided questionnaire data about the sleep difficulties present in their child with AS. Results from this questionnaire confirmed that a variety of sleep problems do exist in AS. These sleep difficulties range from easily awakening by noise, reliance on sleep facilitators, poor sleep initiation, and short sleep duration.
Amount Funded: $3,600
Institution: Cincinnati Children's Hospital

Ethan Bier
Molecular Genetic Analysis of the Drosophila Angelman Syndrome Gene

UBE3A, the gene when disrupted causes AS, is present in all animal and insect species, thus indicating how important it is for normal neuronal function. These investigators were able to identify the equivalent of the UBE3A gene in Drosophila, the fruit fly, and were able to manipulate it and change the expression of UBE3A in such a way that they learned more about other proteins that interact with the Drosophila equivalent of UBE3A. This interaction of other proteins proved to be important in understanding how UBE3A normally acts within brain cells and what happens to brain cells when UBE3A is disrupted.

Arthur Beaudet
A Therapeutic Trial of Folate and Betaine in Angelman Syndrome

One of the unique aspects of the brain problem in AS is that only the UBE3A on the maternally inherited number 15 chromosome is disrupted. The other UBE3A, located on the paternally derived chromosome, is silenced by a control mechanism that involves changes in the DNA and its surrounding proteins. These changes are influenced by differences in their "methylation” status. Methyl molecules (e.g., with the chemical formula of CH3) are important regulators of gene action. ASF has supported attempts to change the methylation status of the UBE3A by providing dietary supplements that increased methyl availability. Two of these agents are folic acid and trimethylamine (Betaine) and this was the earliest human drug trial ever conducted on AS. The result showed minimal benefit of this type of therapy but the study laid the foundation for additional therapeutic trials as described below.
Amount Funded: $62,903
Institution: Baylor College of Medicine

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2002

Soma Das
Molecular Analysis of the Angelman Syndrome: The role of UBE3A deletions

About 90% of individuals believed to have AS will have abnormal genetic tests that identify one of four mechanisms that can disrupt UBE3A function. There are however about 10% of individuals with apparent AS who have negative genetic testing and the question is often raised as to whether other types of undetected genetic mechanisms might be present. ASF supported this study designed to screen for very small deletion regions located within UBE3A (that might have escaped detection previously). The results of the studies showed that it is rare for such small deletions to occur and/or to be missed by existing genetic testing. This project helped clarify which genetic mechanisms do and do not account for a significant number of individuals with AS.
Amount Funded: $25,000
Institution: University of Chicago

Joseph Wagstaff
Role of the UBE3A Gene Product in Brain Protein Metabolism

Dr. Wagstaff was one of the crucial investigators who discovered that UBE3A disruption was the cause of AS. With funds from this and other projects he was able to develop a mouse model for AS and this important development provided a mechanism to learn more about associated proteins in the brain and how proteins change in the brain when UBE3A is disrupted.
Amount Funded: $45,547
Institution: University of Virginia

Stephen Calculator
Efficacy of Enhanced Natural Gestures for Young Children with Angelman Syndrome

Funds for this project built on earlier work by Dr. Calculator (above) and provided additional behavioral treatment strategies to improve communication through nonverbal methodologies.
Amount Funded: $11,541
Institution: University of New Hampshire

Lynne Bird
Folate Clinical Study San Diego Grant

ASF has been aggressive in funding a number of investigators, as well as multiple centers, involved in providing dietary supplements aimed at augmenting the biological availability of methyl groups (see discussion above for Beaudet, 2000). This project helped facilitate clinical trials for families living in the California area and thereby supported the broader U.S. clinical trials conducted in Texas, Boston and other locations.
Amount Funded: $14,145
Institution: University of California San Diego

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2003

Lynne Bird
Folic Acid/Betaine Clinical Study

As noted above, funds for this project represent continued funding for this investigator to conduct expanded clinical trials to attempt to demonstrate the effect of providing methylation-rich dietary supplements to those with AS. Although some positive trends were observed there was no significant difference between the Folic Acid/Betaine group and untreated control group.
Amount Funded: $26,000
Institution: University of California San Diego

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2005

Joseph Wagstaff
Testing for Correction of the Angelman Syndrome Phenotype of UBE3A-Material-Deficient Mice by UBE3A Transgene

This project was continued funding for an important AS investigator to enable his laboratory to work on studies of UBE3A in the mouse model in the hope of developing novel therapeutic initiatives. The experimental approach in this grant was to use genetic engineering so as to insert the human UBE3A into embryonic mouse cells (e.g., create a transgene) and then, ultimately, to attempt therapeutic expression of UBE3A to correct some of the features exhibited by the Angelman mice. Theoretically, this approach would represent a correction of the abnormalities in the mouse model. This research subsequently showed how difficult it was to control and enable transgene expression of UBE3A.
Amount Funded: $47,000
Institution: Carolinas Medical Center

Aaron Razin
Control of monoallelic expression of the Angelman gene UBE3A

The gene disrupted in AS, UBE3A, is unique because its action is controlled by a remote DNA region that is called the imprinting center(IC). In the normal brain, this IC turns off the UBE3A that the father contributed (on chromosome 15) but turns on UBE3A on the number 15 chromosome contributed by the mother. Individuals with AS are thus missing the function of the maternally derived UBE3A. ASF funded this investigator to learn more about how the IC turns UBE3A on and off. This was an effort by ASF to promote molecular research on the IC and complement ASF’s promotion of human clinical trials to provide dietary supplements in hope of modulating the action of the imprinting center. Many publications arose from this work and more evidence supports the fact that the paternal IC is not methylated while the maternal IC is methylated.
Amount Funded: $50,000
Institution: The Hebrew University - Hadassah Medical School

Yong-Hui Jiang
Dissecting the roles of UBE3A in synaptic plasticity by analyzing synaptic function at the single cell level and utilizing 'Network Analysis Proteomics' strategy

This grant-funded research was to a premier AS researcher who was instrumental in developing a mouse model for AS and who demonstrated that an important enzyme associated with the synapse, CAMKII, was inhibited or partially inactivated in Angelman mice. Subsequent experiments by others were able to release this CAMKII inhibition and provided an impressive correction of the features of AS thereby opening the door to the possibility of new therapeutic strategies to treat some of the symptoms of AS. Additional work from this grant showed that the physical structure of the synapse was generally intact and also began to identify additional proteins that interact with UBE3A.
Amount Funded: $56,000
Institution: Baylor College of Medicine

Jane Summers
Evaluating the effectiveness of ABA-based approaches for teaching functional skills to children with AS

For educational planning, it is important to know that children with AS can be effective learners and to understand how this learning occurs under simple paradigms of behavioral modification and analysis. Jane Summers’ work has been instrumental in documenting the learning abilities of those with AS and in illustrating to other educators and therapists how applied behavioral analysis (ABA) can improve learning and change behaviors in AS.
Amount Funded: $47,000
Institution: McMaster Children's Hospital and McMaster University

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2006

Stephen Calculator
Communication/Educational programs for students with Angelman Syndrome in inclusive classrooms: A look at best practices

One of the problems in obtaining optimal educational services for children with AS is that there is not much information regarding placement in inclusive classrooms and in other settings. What can we learn from parents and teachers about their reactions to certain educational placements? This work by Dr. Calculator involved interviews and additional study of selected families and has helped provide the AS community with this information.
Amount Funded: $31,087
Institution: University of New Hampshire

Fen-Ben Gao
Genetic dissection of the Molecular Pathways Underlying the Pathogenesis of Angelman Syndrome

This scientist performed studies on Drosophila, the fruit fly, to determine how UBE3A dosage affects neuron development. The results demonstrated that synaptic connections and dendritic processes are abnormal both when the UBE3A protein is in high and in low amounts. This work helped focus efforts on UBE3A research to the neuron’s synaptic region in the hopes of gaining new insight about how UBE3A is important for normal brain development. This work in combination with previous funding to other investigators (see above for the 2000, Ethan Bier, grant) established the usefulness of the fruit fly as another important experimental model in the study of AS.
Amount Funded: $85,000
Institution: Gladstone Institute of Neurological Disease

Michael Greenberg
Investigation of UBE3A in the role of Synapse Development

We know that UBE3A action inside brain cells is extremely complicated but the research of Dr. Greenberg and his lab has greatly helped to dissect and better understand this complexity. Using mouse models and using powerful genetic technologies to study individual neuron cells, their lab identified new protein targets that regulate synaptic development and activity. Importantly, these new proteins are related to other proteins for which druggable targets have been established and this area of research is creating new ideas about possible new pharmaceutical or other novel types of treatment approaches.
Amount Funded: $85,000
Institution: Children's Hospital Boston

Peter Hammond
Facial phenotype-genotype correlations in Angelman Syndrome

Is there a characteristic or noteworthy facial appearance of individuals with AS? Certainly it is known that those with AS have facial characteristics reflecting the normal traits of their parents but are there subtleties that might lead to an earlier or more accurate diagnosis of the syndrome especially in those for whom genetic testing has not confirmed any abnormality. This work used advanced three-dimensional surface morphology studies and powerful computer analysis to analyze surface modeling of the face in those with AS.
Amount Funded: $10,500
Institution: UCL Eastman Dental Institute

Gentry Patrick
Elucidating the function of the E6AP ligase at mammalian CNS synapses

Work from this grant was part of several projects funded by ASF in order to learn more about UBE3A and its relationship to the larger, complex system of protein degradation (called the ubiquitin-proteasome pathway) that is important to all cellular function. Dr. Patrick's project helped delineate the action of UBE3A-like enzymes in this complex protein degradation pathway.
Amount Funded: $50,000
Institution: University of California San Diego

Lowell Rayburn
Effect of premature truncation of the UBE3A antisense transcript on UBE3A imprinted expression

This grant continued ASF funding to one of the premier AS scientists, Dr. Joe Wagstaff, and his laboratory. The aim of this project was a bold attempt to create therapeutic effects in the mouse model by genetically engineering a control element of UBE3A expression. This element was modified by advanced methods of genetic engineering and embryonic cell treatment. During the course of the study Dr. Wagstaff unfortunately died and this project was discontinued due to the closure of his laboratory and the funds for it returned to the foundation. Dr. Wagstaff was subsequently honored by ASF as an outstanding investigator and ASF now provides grant funding opportunities to young science investigators through the Wagstaff Fellowship program.
Amount Funded: $82,255
Institution: Carolinas HealthCare System

Terry Jo Bichell
Alphabet Therapy

Individuals with AS lack expressive speech and they have difficulty in understanding the structure and complexity of language. This grant provided funding for a project combining intensive behavioral analysis in combination with visual prompts of alphabet letters, numbers, colors and shapes. This project is one of several funded by ASF that affirms the ability of Angelman children to learn when afforded sufficient resources and targeted strategies of instruction.
Amount Funded: $31,300
Institution: Vanderbilt University

Benjamin Enav
A Prospective Pilot Study of Gastric Myolectrical Activity in Children with Angelman Syndrome

This study evaluated individuals with AS to learn more about contractility of the stomach as measured by surface electrical recordings from the abdominal area. The study provides insight into how the stomach contracts before, during and after ingestion of meals and the varied gastrointestinal problems known to exist in AS. One of the findings demonstrated increased periods of diminished or absent stomach contractions (termed “arrhythmias”) when compared to controls. This diminished activity may be fundamentally related to the problem of neuronal imprinting of UBE3A not only in the brain but in other neurons in the peripheral nervous system.
Amount Funded: $30,000
Institution: UCLA

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2007

Yong-Hui Jiang
Explore the therapeutic potential of levodopa to treat AS in mouse model

There is a small amount of anecdotal experience and some neuroscience studies suggesting that levodopa might have therapeutic effect on the symptoms of AS. The Angelman mouse model is an ideal way to study this before developing any human clinical trials and that was the reason for ASF funding this project. The investigator was able to use Angelman mice to investigate effects of levodopa supplementation and in some areas no effect was demonstrated (such as on a type of synaptic activity called long-term potentiation) but in other areas, such as assessment of mouse EEG patterns, an effect was noted. The results did not reveal dramatic effects from levodopa supplementation but did identify areas worthy of further study.
Amount Funded: $50,000
Institution: Baylor College of Medicine

Ronald Thibert
Low Glycemic Index Therapy for the Treatment of Epilepsy in Angelman Syndrome

ASF has supported varied initiatives to improve treatment of seizures in AS and this grant aimed at exploring alternatives to the use of the very restrictive ketogenic diet. In the low glycemic diet, the extremely high lipid content of the ketogenic diet is avoided and more carbohydrates are provided, particularly ones that are more likely to be absorbed at a slower and more stable rate. The hypothesis is that this dietary strategy will allow more stable blood glucose levels and thus improve the control of seizures. This grant has enrolled individuals under 18 years of age in an ongoing clinical study that is providing data on strategies for use of the diet in AS.
Amount Funded: $28,850
Institution: Massachusetts General Hospital

Edward Weeber
Therapeutic effectiveness of levodopa in the treatment of seizures and motor defects using the Angelman Syndrome mouse model

This grant supported a trial of levodopa-carbidopa treatment on AS mice. Levodopa is a dopamine precursor that is converted to dopamine in the brain and is commonly used as a treatment for Parkinson disease. AS mice and normal controls were treated with two different dosages of levodopa-carbidopa or placebo and subjected to tests of motor and cognitive abilities, anxiety and seizure susceptibility. Brain regions were analyzed for Dopamine and other monoamine neurotransmitter levels. Alterations in CAMKII phosphorylation (something that was discovered to be abnormal in the AS mouse model) was also examined. Behavior testing showed an improvement in motor function dependent on treatment, but did not normalize cerebellar-mediated licking behavior. Low-dose levodopa treatment partially rescued motor function but did not completely rescue AS mouse behavioral phenotypes.
Amount Funded: $50,000
Institution: University of South Florida

Elizabeth Thiele
Seizure Survey

Funding for this grant enabled the largest survey ever to be conducted on AS regarding anticonvulsant drug use. This was an extensive questionnaire survey of families within and outside the United States and the results provided important information to families and physicians who seek treatment information about single anticonvulsant drugs and combination drug use for treatment of the seizure problem in AS.
Amount Funded: $10,000
Institution: Massachusetts General Hospital

Edward Weeber
Identifying Potential Therapeutic Strategies for the Treatment of Angelman Syndrome

Dr. Weeber has performed crucial genetic and therapeutic studies on the AS mouse model and was instrumental in conducting one of the first experiments that rescued many of the neurophysiological and behavioral problems of the Angelman mouse. To help build upon this work, ASF provided grant funding to explore a number of potential therapeutic strategies using the Angelman mouse model. These strategies included novel attempts at gene therapy and experiments to explore new protein regulators of UBE3A function. His lab studied neurophysiological properties of hippocampal neurons and also evaluated more global brain regions to evaluate results of these studies. Work from this grant, as well as evidence from other lines of research, show that imprinting of UBE3A in neurons in the mouse brain is quite widespread if not globally distributed.
Amount Funded: $62,200
Institution: University of South Florida

Arthur Beaudet
A rigorous test in the mouse of whether increased DNA methylation can activate neuronal expression of the paternal UBE3A allele

The mouse model provides an ideal way to evaluate therapeutic attempts to increase UBE3A function on the otherwise silenced paternally-derived mouse chromosome. Using novel genetic engineering methods, Dr. Beaudet and his lab were able to develop a engineered mouse with genetic tags on both the paternally and maternally expressed genes, thus enabling a way of detecting more precisely whether drugs or agents are capable of improving activity of the otherwise silenced UBE3A gene. This is part of a number of studies aimed at developing novel treatment strategies for AS.
Amount Funded: $80,000
Institution: Baylor College of Medicine

Margaret Bradley
Brain potentials of cognition and emotion in individuals with Angelman Syndrome

We know that individuals with AS have a propensity for a happy demeanor and often have excessive laughter. We also know that they have pro-social behaviors that are distinctive from other types of genetic conditions. This study evaluated older individuals with Angelman who could cooperate in an experiment whereby subtle regional EEG patterns were studied after certain visual cues were presented. These cues involved pictures of individuals’ faces that were happy, sad or showed other types of visual cues.
Amount Funded: $35,000
Institution: University of Florida

Aaron Ciechanover
The Ubiquitin Ligase E6-AP Targets the Polycomb Repressive Complex Proteins Ring1B and Bmi1 to Ubiquitination and Subsequent degradation: Structural and functional Implications and Possible Relationship to the Pathogenesis of Angelman Syndrome

ASF foundation was proud to sponsor this research by Nobel Laureate Aaron Ciechanover who has been instrumental in characterizing the ubiquitin protein degradation system, a fundamental component of how neurons degrade or adjust proteins in order to function normally. This research focused on the DNA structure and surrounding protein regions of DNA and UBE3A in an attempt to understand how the gene is regulated and what might serve to turn on or repress activity of the gene. Dr.Ciechanover found that indeed Ring1B is a target of UBE3A. How the disruption of Ring1B ubiquitination leads to symptoms in AS is still poorly understood and more work does need to be done in this area.
Amount Funded: $95,000
Institution: Technion University

Michael Ehlers
UBE3A and Altered Neuronal Trafficking in Angelman Syndrome

It is known that UBE3A is important inside brain neurons especially at their membrane surfaces where the synapse facilitates communication between neurons. It has also been recognized that other cellular problems develop when UBE3A is defective and this laboratory identified problems in a protein synthesis and transport system called the Golgi apparatus. Inside the cells of Angelman mice, the Golgi are abnormal and swollen and the work of these investigators provided new insight into UBE3A's relationship to other proteins in the cell.
Amount Funded: $75,000
Institution: Duke University

Brian Kuhlman
Redesigning the Ubiquitin Pathway to Identify the Substrates of E6AP

UBE3A function in the cell has remained elusive especially in terms of how UBE3A protein action relates to other proteins. Thus, researchers have been trying to identify "targets" (meaning proteins) that UBE3A is acting upon in order to either regulate their concentration or cause their degradation. This grant funded a unique method of providing intracellular protein tagging in hopes of identifying UBE3A targets and we learned from this project how difficult it is to identify such targets. This grant and others are part of an effort by ASF to identify UBE3A targets, increase understanding about UBE3A and promote new molecular therapeutic strategies.
Amount Funded: $80,000
Institution: University of North Carolina, Chapel Hill

Sarika Peters
Neuroimaging Studies in Angelman Syndrome

It is known from brain MRI study that there are no obvious malformations associated with AS. However, it is not known if there are more subtle differences in brain development that might provide clues to the action of UBE3A or provide clues as to how some of the behavioral and other intellectual deficiencies might be related to microscopic changes in brain development. This grant involved detailed study of many aspects of brain shape and size, including study of the white matter nerve tracts by use of state-of-the-art MRI imaging. A group of individuals with AS were compared to a group of typically developing individuals. The results indicated presumptive areas of volume changes and white matter abnormalities that are deserving of further study. The investigators presented hypotheses correlating certain behavioral attributes with abnormalities observed from the brain imaging studies.
Amount Funded: $85,000
Institution: Baylor College of Medicine

Benjamin Philpot
Importance of UBE3A for Experience-Dependent Modifications of Cortical Synapses

One way to understand brain abnormalities in those with AS is to actually study individual neurons using state-of-the-art micro-testing methods, for example, measure directly the electrical activities associated with function of the synapse in a single neuron. This technique requires great technical skill and that is the basis of this grant to Dr. Philpot and his colleagues who have experience in understanding and measuring electrical activity of neurons. Studies from this grant provided direct evidence of how neurons can change based on experience (e.g., show neuronal plasticity) and these studies have set the stage for more important work demonstrating in the living Angelman mouse how neurons undergo developmental changes in response to different environmental changes.
Amount Funded: $70,000
Institution: University of North Carolina, Chapel Hill

Michael Stryker
The role of UBE3A in development of excitatory-inhibatory balance in neocortex

The work in this grant extended our knowledge of brain regions that are affected when UBE3A is disrupted. Using the mouse model and studying the visual and brain cortex responses of each eye, this investigator and his laboratory were able to demonstrate how neurons in the visual cortex respond to the imprinting signals of UBE3A and adapt under different circumstances of eye closure and opening. This work, and the work of Dr. Philpot, expands our knowledge of UBE3A's action in the brain and how neurons adjust to changing circumstances and it demonstrates how UBE3A is involved in neural plasticity, a process so important to the acquisition of learning.
Amount Funded: $80,000
Institution: University of California San Francisco

Jane Summers
Developing an assessment battery to study learning, memory and motor performance in children with AS

The work related to this grant extended the long term interest of Dr. Summers in studying how individuals with AS learn and how their behaviors change based on carefully designed behavioral analysis methods in a structured environment. Most importantly, her work has led to development of a standardized and easy to implement assessment battery, specific to AS, which will help to further study and understand learning ability in AS.
Amount Funded: $30,000
Institution: McMaster Children's Hospital and McMaster University

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2008

Chris Oliver
Establishing the basic principles of effective intervention for difficult behavior in AS

What are some of the motivating and reinforcing events that might be used to help children and adults with AS change behaviors? Funding from ASF to Dr. Oliver helps answer such questions. His work has been instrumental in identifying pro-social behaviors and other activities that can be used as rewards and reinforcements to improve problematic behaviors in AS, such as pinching and other types of aggressive or self injurious behaviors. Work from this grant was conducted in the United Kingdom under rigorous programs of behavioral design and control and has clearly pointed out how those with AS have unique behaviors different from those with other types of genetic syndromes associated with intellectual deficiency.
Amount Funded: $78,497
Institution: University of Birmingham

Ype Elgersma
Are the neurological symptoms of Angelman Syndrome reversible? An inducible mouse model for Angelman Syndrome

This grant to Dr. Elgersma and his colleagues, built further upon his earlier significant work demonstrating that many of the neurological and behavioral features of the Angelman mouse model could be reversed by changing the phosphorylation status of an important enzyme located near the neuronal synapse, CAMKII. This project funded a bold effort to establish a new Angelman mouse model that would enable the UBE3A gene to be turned on after an Angelman mouse is born. This research strategy is to learn to what extent the abnormalities in AS might be reversible at some period after the time of birth. If successful, this project would provide a “proof of principle” that therapeutic initiatives might be successful after a child with AS is born. This work is ongoing but has initially met with success in generating the reversible mouse, although studies are pending.
Amount Funded: $76,600
Institution: Rotterdam University

Lynne Bird
Levodopa/Carbidopa Treatment of Children with Angelman Syndrome

ASF has previously supported work at understanding if levodopa might have a potential therapeutic role in AS. This grant provides partial support to a larger clinical trial study which is aimed at implementing a controlled trial of levodopa supplementation to a group of children with AS. Individuals enrolled in the study will have a battery of developmental tests and neurological assessments periodically during a 1 to 2 year treatment phase.
Amount Funded: $68,565
Institution: University of California San Diego

Yong-Hui Jiang
Explore epigenetic therapy of using histone deacetylase inhibitors in the AS mouse model

ASF has supported on many fronts research strategies in an attempt to increase the expression of UBE3A in the AS brain. As discussed for previous grants, it is known that in each nerve cell a UBE3A gene is repressed or silenced and is located on the paternally derived chromosome 15. One way to increase expression of UBE3A is to modify the imprinting control center (located near UBE3A) by trying to induce changes in the protein structure that surrounds or is adjacent to UBE3A. At present, the findings demonstrate that this avenue of gene treatment, while showing some promise, remains problematic since significant expression of the otherwise silenced gene is difficult to obtain.
Amount Funded: $98,450
Institution: Duke University

David Segal
Towards Gene Therapy for Angelman Syndrome Using Artificial Transcription Factors

Dr. Segal has significant experience in synthesizing molecules that bind to DNA and are able to regulate gene activity. ASF has provided funds to this investigator to pursue the possibilities that such agents, called artificial transcription factors, could have an effect of increasing the expression of paternal UBE3A. These transcription factors could operate either very close to UBE3A or in regions some distance away, for example where the imprinting control center is located. To date, although preliminary work was encouraging, no viable transcription factor has been identified that brings about significant activation of the otherwise silenced UBE3A.
Amount Funded: $76,055
Institution: University of California Davis

Eric Klann
Neuregulin-dependent Alterations in Glutamate Receptor Function and LTP in Angelman Syndrome Model Mice

How can we better understand the problems of intellectual deficiency in AS? Recently it has been clear that one key to answering this question resides in better understanding of how neuronal synapses function. Neuregulins are important proteins involved in synapse function as they help reorganize and fully develop the synapse so that it is better able to respond to the types of stimulations and experiences that result in learning and memory. Dr. Klann's studies have delineated how neuregulins relate to synaptic development and how neuregulins are affected in the Angelman mouse model, and they provide one more important link to our better understanding of the synapse problems in AS.
Amount Funded: $78,788
Institution: New York University

Michael Ehlers
Restoration of Neocortical Plasticity In a Mouse Model of Angelman Syndrome

In this research project, AS mice were studied at the time of birth and throughout the early days of life under controlled conditions that create different degrees of visual experience. This project was funded in collaboration with Dr. Philpot (see below) and extended further our understanding or how AS neurons behave and change under different stress conditions. In this situation, AS mice were housed in light and dark environments. Their neurons in the visual cortex were studied to document electrophysiological changes in single neurons. This work proved that AS neurons can undergo favorable developmental changes under certain conditions.
Amount Funded: $95,000
Institution: Duke University

Benjamin Philpot
Restoration of Neocortical Plasticity In a Mouse Model of Angelman Syndrome

An important question about the developmental problems in AS is to what extent neurons change based on experience and how this is impaired in AS. One way to understand this is to use the Angelman mouse model to study neurons in the occipital visual cortex and determine how they adjust and adapt to new visual stimuli (see above for Michael Ehlers). The work involved measuring cell activity using exquisite methods of micro manipulation and electrical recordings of individual neurons. This work was important in establishing that under certain experimental conditions the neurons from mice with AS were capable of achieving relatively normal electrophysiological activity.
Amount Funded: $95,000
Institution: University of North Carolina, Chapel Hill

Lawrence Reiter
A combined molecular and electrophysiological approach to understanding cerebellar defects in AS

Individuals with AS have movement problems and are unstable walking. These findings have suggested that the cerebellum plays an important role in AS in causing these problems. In the Angelman mouse model, cerebellar function can be studied through the use of certain coordinated repetitive behaviors such as feeding and licking behaviors and that has been the basis for these studies. The purpose of this grant is to study these behaviors in the Angelman mouse model combined with detailed histological and protein chemistry studies of cerebellar neurons, and other neurons and cells in other brain regions.
Amount Funded: $77,866
Institution: University of Tennessee Memphis

Ronald Thibert
The Significance of EEG Findings in Angelman Syndrome

It is known that individuals with AS have an abnormal EEG during periods when seizures do not occur as well as when seizures do occur. Although the patterns of EEG abnormalities have been previously described in AS, there has been little work that correlates EEG patterns to the severity of epilepsy, or that compares individuals with AS who have different genetic mechanisms. This project analyzes many EEGs from individuals throughout the United States. This work builds upon previous experience this investigator has had in AS through involvement in a survey-based analysis of seizures among the Angelman community (see above).
Amount Funded: $58,256
Institution: Massachusetts General Hospital

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2009

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

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.
Amount Funded: $40,269
Institution: Vanderbilt University

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

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.
Amount Funded: $64,269
Institution: University of Nebraska Medical Center

Benjamin Philpot
Novel therapeutics for AS by manipulating UBE3A expression

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.
Amount Funded: $199,972
Institution: University of North Carolina, Chapel Hill

John Marshall
Rescue of Angelman Syndrome Learning Deficits by an Investigational New Drug

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.
Amount Funded: $198,899
Institution: Brown University

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

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.
Amount Funded: $197,580
Institution: New York University

Peter Howley
Identification of UBE3A Ligase Substrates

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 lnew UBE3A protein targets, providing additional possibilities for new therapeutic strategies in AS.
Amount Funded: $200,000
Institution: Harvard Medical School

Yong-Hui Jiang
Novel UBE3A Isoform and Angelman Syndrome

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.
Amount Funded: $99,425
Institution: Duke University

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

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.
Amount Funded: $94,563
Institution: Texas A&M University

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