The Kendall Morgan FAST-TRAC (Targeted Research to Advance a Cure) Award

“Effectiveness of established therapeutics for the treatment of Angelman Syndrome”
Awarded to: Edwin Weeber, Ph.D., Department of Molecular Pharmacology and Physiology, University of South Florida.

Dates: December 1st, 2010 – November 30th, 2011 (extended through 2012)

Summary: There is mounting evidence to suggest that a treatment for Angelman syndrome is not just possible, but probable. The lack of known molecular targets associated with AS has hampered the development of specific therapeutics. However, a recent surge of potential therapeutics for other disorders associated with cognitive disruption has begun to be used in human clinical trials. The molecular modes of action for many of these new therapeutic agents have correlates to counter the molecular defects observed in AS. Thus, this proposal seeks to determine the effectiveness of compounds that are FDA approved and currently being used in clinical trials on the well-established AS mouse model. We propose to look at 4 of these compounds at the level of: 1) Degree of cognitive enhancement. 2) Rectification of a biological and genetic abnormality. 3) Increase in synaptic function and/or plasticity. It is our hope that these compounds will have a positive effect on one or more of these aspects. Furthermore, any positive results will prompt a full preclinical evaluation of the compound(s) and may lead to the development of an effective AS therapeutic.

Publications Associated with this Funding:

The Innovative Mag-Drive Grant-In-Aid

“Angelman Syndrome Biomarkers for Therapeutic Treatments”

Awarded to: Walter C. Low, Ph.D. and Jason B. Nikas, DPT Program for Neuroscience and Departments of Neurosurgery and Physiology at the University of Minnesota

Dates: March 7th, 2011 – March 7th, 2012

Amount: $2,500

Summary: Angelman Syndrome (AS) is a neurodevelopmental disorder with genetic causes. It has been observed that altered gene interactions within different areas of the brain give rise to the symptoms characteristic of AS patients. The focus of the study will be to investigate and discover how genes interact with each other in the area of the brain known as the hippocampus. This brain area is involved in learning, and it is of major significance and relevance to the pathology of AS. We will study tissue from the hippocampus area of the brain from normal and AS subjects. By identifying which gene interactions are dysregulated in the case of AS subjects as compared with normal subjects, we will be able to find a number of possible approaches to intervene and steer the responsible gene interactions toward a normal state. We think that some of those approaches will have the potential to lead to therapeutic treatment for AS patients. We have developed a biomarker platform technology that is capable of identifying not only genes that play a significant role in a given disease but also how those genes are interconnected, how they influence each other, and in what way their networks and overall function differ from the normal state. By applying out technology to the area of AS we think that we will be able to 1) identify the altered gene networks responsible for AS in the hippocampus and 2) find possible targets for therapeutic development to influence those altered gene networks toward a normal pattern.

The Christina Castellana FAST Postdoctoral Fellowship Award

“Targeting Upstream Regulators of Ube3a in Angelman Syndrome”

Awarded to: Jason J. Yi, Ph.D., Department of Pharmacology, University of North Carolina School of Medicine, Co-mentors: Klaus M. Hahn, Ph.D. and Benjamin Philpot, Ph.D.

Dates: June 1st, 2011 – May 31st, 2014

Amount: $164,000

Summary: As an E3 ubiquitin ligase, Ube3a catalyzes a reaction to label certain proteins in the cell so that they are targeted for degradation. Mutations that abolish this activity are sufficient to cause Angelman Syndrome (AS). Typically, ubiquitin ligases recognize several substrates, and numerous substrates of Ube3a have been proposed. Thus, Ube3a likely regulates an ensemble of proteins that contribute to AS pathogenesis, and therefore, targeting individual components of this group for AS therapies may not be sufficient to alleviate neurological deficits associated with AS. Increasing evidence suggests that abnormal variations in the quantity of Ube3a itself may be at the heart of neurodevelopmental diseases. UBE3A resides within chromosome 15q11-13, a heavily imprinted genomic region associated with a variety of neurodevelopmental disorders. In the brain, Ube3a is only expressed from the chromosome inherited from the mother. Children who inherit a maternal chromosome carrying a deletion in 15q11-13 develop AS, whereas the majority of children who inherit a maternal chromosome carrying duplications in 15q11-13 develop Autism spectrum disorder. Therefore, understanding the factors that control the cellular quantities of Ube3a may provide an effective strategy for the design of AS therapeutics. My preliminary work has found that Ube3a stability is subject to regulation by enzymes that act upstream of Ube3a. This identifies for the first time biological mechanisms within cell that function to maintain cellular Ube3a quantities. I have proposed a system of experiments that investigates how Ube3a misregulation leads to learning defects in individuals with AS. My approach will use recent advances in biosensor development as well as sophisticated microscopy techniques to visualize directly in the brain how loss of Ube3a function perturbs normal events that occur during learning and memory at synapses. Moreover, these experiments will simultaneously allow me to identify pharmacological targets for AS therapy, and test how manipulation of these targets affects the properties of neurons lacking Ube3a. I expect that these experiments will provide insight into previously unknown mechanisms of AS pathogenesis and provide novel targets for the development of therapeutic strategies in AS. The ultimate goals of these studies is to (1) identify the molecular casus of AS by understanding Ube3a regulation and (2) using this information, develop potential pharmacological strategies for AS treatment.

Publications associated with this funding:

FAST Postdoctoral Fellowship Award

“Exploring FDA Approved Therapeutic Strategies for the Treatment of Angelman Syndrome”

Awarded to: Justin Todd Rogers, Ph.D. Department of Molecular Pharmacology, University of South Florida
Mentor: Edwin J. Weeber, Ph.D.

Dates: June 1st, 2011 – December 31st, 2012

Amount: $108,000

Summary: There is a growing consensus in the scientific community that believes that a treatment for Angelman syndrome (AS) is not just possible, but very probable. However, the lack of known therapeutic targets at the cellular level that underlies the mechanisms of AS has hampered the development of therapeutic strategies. Couple that with the laborious and timely task of obtaining FDA approval once a therapeutic strategy is found, it quickly becomes evident that a treatment for AS is years or maybe even decades away. With these roadblocks in mind, this proposal tries to circumvent both of these deficiencies in regard to successfully and responsibly developing a therapeutic strategy for the treatment of AS. In this regard, this proposal does not focus, necessarily, on understanding mechanisms of AS but rather treating AS. Two main concepts were taken into consideration when I developed this proposal: shortening the time to elucidate the underlying mechanisms of AS and shortening the amount of time to have a therapeutic strategy FDA approved. This was accomplished in two ways; 1) Use pharmacological agents that are known have correlates to counter the molecular or cognitive deficiencies involved with AS. 2) Use pharmacological agents that are already FDA approved for use in humans and have an established treatment regimen. The use of these two strategies will significantly reduce the amount of time from experimental testing, to preclinical evaluation to a working and publicly available treatment for AS. To test the validity of these compounds, the AS mouse model will be used and four compounds tested and treated AS mice compared to wild-type mice at the levels of 1) Degree of cognitive enhancement 2) Rectification a biological and genetic abnormalities 3) Increases in neuronal connectivity and neuronal efficiency. It is my hope that one of these compounds will have a positive effect on one or more of these aspects that underlie AS. Furthermore, any and all positive results will prompt a full preclinical evaluation of the compound(s) and could potentially lead to the development of an effective AS therapeutic strategy.

FAST-TRAC (Targeted Research to Advance a Cure) Award

“Minocycline Pre-Clinical Animal Studies”

Awarded to: Edwin Weeber, Ph.D., Department of Molecular Pharmacology and Physiology, University of South Florida.
Dates: June 30th, 2011 – June 30th, 2012

Amount: $14,795

Summary: The previous FAST-TRAC award to Dr. Weeber identified minocycline as a potential therapeutic for Angelman Syndrome; reversing deficits of learning, memory, and motor skills in the AS mouse model.  This award provide additional funds to repeat these studies and increase the number of mice analyzed and add additional testing methods for testing the efficacy of minocycline in this model.  These studies will form the basis of the application for IRB approval for a potential clinical trial of minocycline in patients with AS.

Publications associated with this funding::

FAST Postdoctoral Fellowship Award

“Epigenetic Repression of the Paternal Ube3a allele in neurons”

Awarded to: Sarah G. (Black) Christian, Ph.D. Department of Veterinary Pathobiology, Texas A&M University
Mentor: Scott V. Dindot, Ph.D.

Dates: June 1st, 2012 – June 30th, 2015

Amount: $164,000

Summary: Angelman syndrome (AS) is a devastating disorder characterized by severe intellectual disability, absence of speech, abnormal gait, seizures, and inappropriate laughter. Loss of function or loss of expression of the maternal, but not paternal, UBE3A allele results in AS due to genomic imprinting of the gene in the brain. The mechanisms regulating genomic imprinting of UBE3A remain poorly understood. To address these important questions, our laboratory has initiated a number of molecular, epigenetic and genetic studies to identify factors regulating genomic imprinting of Ube3a in the brain. In our preliminary studies, we have found that Ube3a is expressed from both paternal and maternal alleles in neural stem cells (NSC) within the hippocampus of mice. Differentiation of these stem cells leads to repression of the paternal allele in neurons, but not in astrocytes. In specific aim 1, we will utilize RNA interference technology to identify epigenetic modifiers initiating and maintaining repression of the paternal Ube3a allele in neurons. Results from this study will provide valuable insight into the fundamental mechanisms regulating genomic imprinting of Ube3a in the brain and may provide the foundation for therapeutic strategies aimed at reactivating the paternal UBE3A allele in AS patients.

FAST-TRAC (Targeted Research to Advance a Cure) Award

“Efficacy of Minocycline for the Treatment of Angelman Syndrome”
Awarded to: Edwin Weeber, Ph.D., Department of Molecular Pharmacology and Physiology, University of South Florida.

Dates: March 1st, 2012 – March 1st, 2013
Amount: $180,000
Summary: Angelman syndrome is a rare genetic disorder characterized by phenotypic traits such as global developmental delay, ataxia and seizure. Children diagnosed with AS display a behavioral profile consisting of a happy demeanor with easily provoked laughter and hyperactivity. Building on our previous FAST-TRAC studies, the objective of this study is to examine the efficacy of minocycline to improve the cognitive and behavioral deficits of the Angelman Syndrome participant. Currently, the only treatment available for AS patients consists of supportive care including seizure control and behavioral therapy. Our laboratory has collected data indicating improved motor function and cognition after the administration of MC as well as enhanced synaptic function. Further, previously published data suggests the administration of MC to children with other genetically based neurologic disorders (e.g.Fragile X syndrome) dramatically improved dendritic spine morphology and behavioral performance. Taken together, we posit, children treated with MC will experience the same beneficial effects observed in previous studies and the AS mouse model.
Clinical Trial Completed in March 2013

Publications associated with this funding:

FAST Grant-In-Aid

“Targeting Upstream Regulation of Ube3a in Angelman Syndrome”

Awarded to: Mark Zylka, Ph.D. Department of Cell and Molecular Physiology, The University of North Carolina at Chapel Hill

Dates: July 1st, 2012 – June 30th, 2013

Amount: $20,000

Summary: This award supports the work of Christina Castellana FAST Postdoctoral Fellow Jason J. Yi, Ph.D., by providing funds to cover supplies and service costs associated with the project.

FAST Grant-In-Aid

“E6-AP Transcriptional Targets in the Pathogenesis and Therapy of AS”

Awarded to: Zafar Narwaz, Ph.D. Department of Biochemistry and Molecular Biology, University of Miami
Dates: February 1st, 2013 – January 31st, 2014

Amount: $41,460

Summary: Angelman syndrome (AS) is a complex genetic disorder that affects the nervous system. AS affects an estimated 1 in 12,000 to 20,000 individuals. Characteristic features of AS includes developmental delay or intellectual disability, severe speech impairment, seizures, small head size, and problems with movement and balance. Deregulation of the expression of a protein called E6 Associated Protein (E6-AP) is tightly associated with AS. E6-AP has been described to have two functions: the first is a function that mainly leads to the degradation of other proteins, and the second, first described by us, is to activate the DNA transcription of other genes through steroid hormones and their receptors like Estrogen Receptor alpha. Up till now, most of the published studies have examined the role of first function of E6-AP in the development of AS and it is not known if the second function of E6-AP plays a role in the pathology of AS. In this grant application, we will examine the role of the transcriptional coactivation function E6-AP through Estrogen Receptor alpha signaling in the development of AS. We have taken an interdisciplinary approach by connecting the steroid hormone-signaling field with neuroscience, from which we expect to find exciting results that would hugely impact future research on both fields. This will provide us with valuable information on the currently unidentified downstream effectors of E6-AP. Identification of pathways that are transcriptionally regulated by E6-AP would also lead to the development of novel targeted molecular therapies for AS. Our novel proposed hypothesis is based on extensive evidence indicating that E6-AP has two important biological roles, which the research community has failed to connect: 1) E6-AP is a known coactivator for Estrogen Receptor and 2) E6-AP is a gene associated with AS. Innovation, in this grant application, is mainly presented by focusing on the transcriptional co-activator function of E6-AP through Estrogen Receptor. We believe that the combination of such an innovative idea with practical standard methodologies will greatly contribute to the feasibility of the proposed studies. This project will provide a prime source for the discovery of new molecular pathways and their role in neuropathology of AS. Accomplishing the proposed studies in this grant will not only provide new insights into the mechanism of action of E6-AP and ER in AS but will also provide promising new therapeutic targets and venues for AS patients.

FAST Integrative Research Environment (FIRE)

“Identification and Characterization of Novel Therapeutics for Angelman Syndrome”

Awarded to:

Anne E. Anderson, M.D. Departments of Pediatrics, Neurology and Neuroscience, Baylor College of Medicine

Scott V. Dindot, Ph.D. Department of Molecular and Cellular Medicine, Texas A&M University

David J. Segal, Ph.D. Departments of Biochemistry, Molecular Medicine, and Pharmacology, The University California at Davis

Edwin Weeber, Ph.D., Department of Molecular Pharmacology and Physiology, University of South Florida.

Kevin Nash, Ph.D., Department of Molecular Pharmacology and Physiology, University of South Florida.

Dates: May 1st, 2013 – April 30th, 2016

Amount: $2,547,368

Summary: Angelman syndrome (AS) is a rare genetic disorder that presents with seizure, ataxia and severe mental retardation, and is genetically and biochemically associated with other cognitive disorders such as autism and Fragile X syndrome (Clayton-Smith and Pembrey 1992; Curia, Papouin et al. 2009). There is currently no known treatment of AS.  AS arises through the genetic or biochemical disruption of the maternal UBE3A allele, which when coupled with typical epigenetic silencing of the paternal UBE3A allele, gives rise to an absence of Ube3a protein in the CNS (Kaplan, Wharton et al.1987; Buiting, Saitoh et al.1995; Matsuura, Sutcliffe et a. 1997; Gustin, Bichell et al. 2010). Our research suggests that intervention in adult AS mice has the potential to rescue the cognitive and behavioral phenotypes prevalent in the AS mouse model (Daily, Nash et al. 2011). The current proposal is focused on short- to long-term development of potential therapeutics and identification of novel therapeutic targets for the treatment of Angelman syndrome.  A particular emphasis is made in three area of research: a) identifying drug precursors that can activate the silenced paternal Ube3a allele; b) evaluating pre-existing therapeutic agents of efficacy in improving behavioral, cognitive and synaptic plasticity defects and reducing seizure/epilepsy propensity; and c) determination of new molecular targets for AS intervention. These aims will be performed using the Ube3a maternal deficient mouse model of Angelman syndrome.  Concurrently, we will engineer a rat model of the disorder in order to compliment this mouse model and propel therapeutic development efforts for AS forward.

Publications associated with this funding:

The Jamie K. Berkley Memorial Grant-In-Aid

“Imaging Equipment Upgrade for the Analysis of Therapeutic Proteins”

Awarded to: David J. Segal, Ph.D. Genome Center, The University of California at Davis
Dates: August 19th, 2013 – One time award; equipment

Amount: $9,029.70

Summary: The Segal Lab at the UC Davis Genome Center has created a potential treatment of Angelman Syndrome by creating an injectable protein that allows the brain to produce the protein Ube3a. The lack of Ube3a has been determined to be the root cause of AS and there are indications that if it is restored, some alleviation of symptoms may by possible.  Significant progress has been made in a mouse model of Angelman Syndrome, and future work will extend these efforts to rat models as well as human cells. This Grant-in-Aid will enable equipment upgrades to be purchased to overcome a critical current limitation in visualizing the RNA and protein levels of Ube3a in the brain following treatment.  Since the Segal Lab has specialized in creation of targeted gene approaches to various molecular studies, these upgrades will allow the group to more rapidly evaluate test results and determine the effectiveness of the proposed treatment.

FAST Grant-In-Aid

“Angelman Literacy and AAC Camp”

Awarded To:  Dr. Caroline Musselwhite, Dr. Gretchen Hanser, Erin Sheldon, M.Ed.

Dates:  August 5th, 2014 – August 4th, 2015

Amount:  $20,000

This project aims to gather empirical data on how assistive technology can support literacy and communication development in school-aged children with Angelman syndrome, in order to inform ongoing development of effective interventions for this population.  Data gathered from this camp will contribute to the development of reliable evaluation models for students with Angelman syndrome. This camp provides an opportunity to field-test and refine existing assessment tools and to examine the role of assistive technology in more accurately assessing this population. We will evaluate students in the areas of phonological and phonemic awareness, developmental writing, and the use of symbols in communication. We will test the use of existing assessment tools such as early conventional literacy measures (e.g.: the QRI) and emergent measures, such as the Bridge Observational Rating Scales, the Developmental Writing Scales, Developmental Spelling Test, Pragmatics Profile, the Kovach AAC Profile, the Staugler Literacy Rubric, the Hanser 7 point rating scales, and more. Adults will be trained to self-assess their own support behaviours.

FAST Postdoctoral Fellowship Award

 “Development of Non-Invasive Screening and Diagnostic Tests for Angelman Syndrome”

Awarded To: Jimmy El Hokayem, Ph.D.

Mentor: Zafar Nawaz, Ph.D.

Dates: December 1st, 2014 – November 30th, 2015

Amount: $56,000

This project aims to develop the use of hormones as biomarkers in the screening and diagnosis of Angelman Syndrome (AS) (prevalence 1/15000). There is an unequivocal need for an affordable, noninvasive and reliable biomarker that can predict the onset of or diagnose AS. Our novel basic science research work suggests that certain hormone levels are rendered abnormal in the pathobiological course of this disease, thus rendering these hormones as testable screening biomarkers for AS. Thus, quantitation of hormone levels, via High Performance Liquid Chromatography (HPLC) or any other validated method, in human blood samples could be used as a screening, as well as a diagnostic tool for AS, and maybe other neurological disorder. To our knowledge, the “Use of hormones as a biomarkers for screening and diagnosis of AS” is a highly innovative idea with an exciting potential. To accomplish this objective, we have set the following specific aims: 1- To establish, in house, quantification of hormone levels in blood samples of normal humans via HPLC based on an already published method in the literature. 2- To compare hormone levels in AS patients versus their normal siblings. The timeline of this project is summarized as follows: Aim 1 is predicted to be completed the first 3 months of year 1. Aim 2 is predicted to be started on the second month of year 1 and completed by end of year 1. As for the therapeutic significance, the need for a non-invasive routine AS screening test during the first months of infancy and at later age, and the need for an affordable molecularly defined diagnostic test are highly warranted for AS. As for the group of patients that has been identified with AS on clinical basis only, this kind of molecular test is highly necessary. Thus, hormone markers could be instrumental in: 1- Affordably screening and predicting incidence of AS in infants starting day one after birth, and possibly even before birth. 2- Allowing possible prophylactic and protective clinical measures to be taken before onset of disease in cases where test is positive in infants. 3- Opening the door to research related to prophylactic measures that can be taken to prevent or to alleviate onset of symptoms seen in AS. 4- Possibly providing molecular basis for AS cases that are solely diagnosed on a clinical basis. 5- Possibly presenting a new reliable diagnosis tool for AS.

FAST Australia Grant-In-Aid

RNA binding motifs as therapeutic targets for Angelman Syndrome

Awarded To:  Joel Mackay, Ph.D., School of Molecular Biosciences, University of Sydney

Dates:  January 1st, 2015 – March 12th, 2016

Amount:  $265,619

The underlying cause of Angelman syndrome (AS) is the loss of the maternal copy of the gene UBE3A. In neurons throughout the brain, the paternal allele is intact, but is silenced by the UBE3A antisense transcript (UBE3A-ATS). Reactivation of the silenced allele is therefore a high therapeutic priority, as its restoration is expected to ameliorate much of the AS pathology. This proposal will investigate the mechanism by which the UBE3A-ATS achieves silencing of UBE3A, which is currently unknown. We hypothesize that UBE3A-ATS silences UBE3A by an epigenetic mechanism that involves the 3′ end of UBE3A-ATS. The two most likely candidate mechanisms will be explored in Aims 1 and 2. In Aim 3, first steps will be taken towards the design of inhibitors that could lead to a potential therapy for AS that addresses the primary genetic cause.

Aim 1. Discover whether specific sequences in UBE3A-ATS are important for silencing. CRISPR/Cas nucleases will be used to systematically mutate regions along the 3′ end of the UBE3A-ATS gene. The effect on UBE3A expression will be determined by strand-specific RT-PCR.

Aim 2. Identify proteins that bind to the 3′ end of UBE3A-ATS. We will screen a neuronal nuclear extract for proteins that specifically interact with the 3’ end of UBE3A-ATS. The influence of identified proteins on silencing will be assessed in functional assays.

Aim 3. Lay a foundation for the design of inhibitors of the silencing mechanism. If we identify protein partners of UBE3A-ATS, we will disrupt the interactions using CRISPR/Cas nucleases in a neuronal cell culture model derived from patients with AS. Epigenetic marks will be determined by bisulfite sequencing or chromatin immunoprecipitation (ChIP) at the UBE3A locus. These experiments will establish whether inhibition of such UBE3A-ATS-protein interactions represents a promising therapeutic strategy.

FAST Grant-In-Aid

“Development and characterization of a pig model of AS”

Awarded To:  Scott V. Dindot, Ph.D. Department of Molecular and Cellular Medicine, Texas A&M University

Co-funded by FAST and FAST Australia

Dates:  March 1st, 2015 – February 29th, 2016

Amount:  $201,720

Loss of the maternally inherited ubiquitin E3A ligase (UBE3A) gene causes Angelman syndrome (AS), a devastating neurological disorder characterized by intellectual disability, ataxia, absent speech, seizures, and a happy disposition [1]. The UBE3A gene is imprinted with maternal-specific expression in the brain and biallelic expression in all other cell types. Consequently, mutations affecting the maternal UBE3A allele cause AS, whereas mutations affecting the paternal allele are non-penetrant. Currently, there are no effective therapies to treat AS patients. There are, however, a number of promising therapeutic strategies recently identified using mouse models of AS. Huang et al. (2011) demonstrated that topoisomerase inhibitors — chemotherapeutic agents used to treat cancer — reactivate the paternal Ube3a allele in the adult mouse brain [2]. Topoisomerase inhibitors are highly toxic, so their use as an AS therapy at this point is unclear. Nevertheless, this study demonstrated that the Ube3a imprint is amendable to pharmacological intervention and may serve as a viable AS therapeutic. Daily et al. (2012) showed that gene therapy improves cognition in adult AS mice, indicating that AS is indeed treatable [3]. There are currently numerous laboratories working to identify therapies for AS, including treatments that have shown promise in mouse models of other conditions (e.g., Rett and Fragile-X syndromes); however, there is a critical need for preclinical models more physiologically similar to humans to validate and evaluate these promising therapeutics. Here, we propose to develop and characterize a pig model of AS. Our long-term goals are to understand the pathogenesis of AS and develop therapies to treat this debilitating condition. Our central hypothesis is that the AS pig model will recapitulate many of the phenotypes characterized by AS, and serve as a final-stage preclinical model for testing promising therapeutics. The objectives of this proposal are to generate a pig model with a loss-of-function mutation in the porcine UBE3A gene and characterize it for AS relevant phenotypes.

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