cure

Our C.U.R.E.-AS funding philosophy stands for Collaborate, Understand, Ready and Expedite. We are driven by the rapidly developing science to ensure our spending aligns with the greatest ROI to accelerate our mission to find a cure. Thanks to our FAST community we are happy to share that since our founding in 2008, FAST has funded research and initiatives totaling $26.6M.

In 2020-2021, we have funded over $3M in grants to advance our roadmap to C.U.R.E.-AS.

FAST is always exploring the latest in technology and science to ensure no stone is left unturned. We know we have a promising roadmap as confirmed by our long time FAST researchers Dr. Segal and Dr. Wilson.

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Here is what our FAST community’s donations have funded:

Grantee

Grant

Researcher

Funding

Collaborate

Colorado Children's Hospital

Emergency Care Consortium

Dr. Jessica Duis

$383,163

Understand

University of Southern Florida

hUBE3A, SlUB, SUB Comparison Gene Therapy for AS

Dr. Kevin Nash

$110,000

University of Pennsylvania

MiRNA mediated down regulation of the Ube3a-AS to increase UB3a protein levels in neurons.

Dr. Jim Wilson

$343,751

Ready

Texas A&M Agrilife Research

Translational Research in Pig Model of AS

Dr. Scott Dindot

$271,929

North Carolina State University

Human platform to effficiently study Class 1 Deleted Genes

Dr. Albert Keung

$149,661

Yale University

Generation & characterization of a new large deletion AS mouse model.

Dr. Yong-Hui Jiang

$233,299

Yale University

A biorepository of AS human iPSC neuronal cell lines.

Dr. Yong-Hui Jiang

$346,705

Duke University

Outcome measurement assessment for patients with AS.

Dr. Bryce Reeves

$77,875

Research Triangle Institute/ Boston Children's Hospital

Accelerating data analysis and publications from Natural History Study

$14,454

Research Triangle Institute

Adding AS, Prader-Willi and DUPlSQsyndromes to Early Check Newborn Screening Panel

$378,767

North Carolina State University

lsogenically controlled human cell lines targeting aberrant imprinting genotypes and a new reporter cell line.

Dr. Albert Keung

$173,139

Expedite

University of California/Davis

FAST lnfrastructu re/Dedicated Lab

Dr. Dave Segal; Dr. Jill Silverman; Dr. Kyle Fink

$597,351

University of California/Davis

IND Enabling studies for HSC therapy in AS.

Dr. Joe Anderson

$496,540

2021 Grants Funded

$3,576,634

Collaborate: FAST is committed to 360° collaborations. This includes sharing research, trial and organizational updates with families, researchers, pharmaceuticals, physicians/clinics, FAST Global and ASF to promote, engage and encourage progress toward our mission to find a cure.

Emergency Care Consortium

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The Emergency Care Consortium is FAST funded by a multiple-year contract and aims to provide services in emergency and urgent situations for patients with AS. The consortium is available 24 hours a day and 7 days a week and can be reached at (800-525-4871). The goal of this consortium is to ensure that all patients with AS get the best care possible no matter where they are located (worldwide). By calling this number, families are provided with a formal process that connects medical providers to experts familiar with AS management and current protocols – particularly in emergency seizure situations.

Understand: FAST is committed to investigating, identifying and funding research opportunities leading to numerous human therapeutic candidates. Establishing an infrastructure to support pre-clinical work to lead to potential human benefit.

hUBE3A,STUB,SUB comparison gene therapy for Angelman Syndrome

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Many in the AS community are very familiar with that AS syndrome is caused by the absence or disruption of the UBE3A gene in the brain causing a missing or non-functional UBE3A protein leading to the symptoms of Angelman syndrome. Dr. Nash is currently working on a project to research the impact UBE3A has not only within the neurons but also outside of them. This project seeks to understand the different approaches to the replacement of UBE3A including cross-correction, extracellular, and the standard uUBE3A neuronal gene replacement. But before getting into larger impacts, what are these different types of replacements?

Cross-correction replacement works by secreting a copy of UBE3A outside the neuron, which is modified to be taken up by surrounding neurons. This has the potential to impact many more neurons than standard gene replacement therapy. Extracellular delivery of Ube3a is more similar to enzyme replacement therapy, where you can deliver the protein outside the neurons and see the impact the protein has at the synapse, between the neurons. Standard hUBE3A (human UBE3A) neuronal gene replacement is the gene therapy most commonly thought of and replaces the copy of UBE3A directly in the neuronal cell, ideally in the nucleus of the cell. Bringing this back to the bigger picture for AS, this project has incredible value in understanding how these different gene replacement therapies impact brain function, as 2 different cross-correction programs have shown incredible promise in the animal models. As future gene therapy programs come online, this project can provide essential research into the different needs for UBE3A in the brain.

MiRNA mediated down regulation of the Ube3a-AS to increase Ub3a protein levels in neurons.

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Dr. Wilson, at the Gene Therapy Program of the University of Pennsylvania, is currently developing a potential therapeutic approach for Angelman syndrome (AS) with the use of microRNAs. MicroRNAs (miRNAs), are a class of non-coding RNAs that play roles in gene regulation, to downregulate the UBE3A antisense-transcript (UBE3A-AS). This method has the potential to provide a permanent approach to paternal gene activation.

Additionally, a proof-of-concept study, or a study that provides evidence that treatment could potentially be successful in later stages of development, also uses miRNAs against human/non-human primates UBE3A-AS, and these methods will be developed and tested in AS patient neurons. This is an exciting step for gene therapy within the Angelman syndrome community and we continue to look forward as a potential  treatment option.

Ready: Establish and maintain an enduring framework to ensure the most robust animal models are created for testing, clinical endpoints and biomarkers are sensitive and meaningful, all genotypes are de-risked and tested, and clinical trial readiness is maximized

Translational Research in Pig Model of AS

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Texas A&M University is currently working towards characterizing an Angelman syndrome (AS) pig model. The current pig model was established under another FAST-funded effort and the next step forward is with Dr. Dindot striving to develop, test, and validate potential therapies for AS. Animal models continue to provide opportunities for scientists to better understand the underlying mechanism of AS and Dr. Dindot specifically will be using this model to assess any behavior changes seen after either activating the paternal copy of the UBE3A gene or replacing the material copy. Pigs are incredibly smart animals with anatomy and physiology more similar to that of humans, compared to the numerous rodent models available. The AS pig model is capable of showcasing AS symptoms, like cognition, communication, gait, seizures, etc., all of which can and will be evaluated in this research effort.

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Human platform to efficiently study Class 1 Deleted Genes

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The majority (about 70%) of individuals with AS have a large deletion on the maternal copy of chromosome 15, encompassing the UBE3A gene, yet also including an additional number of genes outside of UBE3A. These are an important set of genes to study since they are the genotype of such a large percentage of AS patients, and understanding the impact they have on the symptoms of AS, outside of UBE3A can drive the need for future, or additional, therapeutics for this population of patients. Dr. Keung from NC State is currently working on a human platform to efficiently study these deleted genes. The goal of this project is to create a human platform, or human model, that can be used to study the deletion of UBE3A and the surrounding genes. The creation of a ‘landing pad’ is paramount in this study, but what does that mean exactly? Similar to the landing pad used by helicopters when they are touching down after flight, a genetic landing pad is a piece of DNA that has no specific function by itself but has been designed to secure and accelerate the integration of genes that are inserted into the DNA. Genetic constructs with intact UBE3A and those surrounding genes that have been deleted can then be inserted into human induced pluripotent stem cells (hiPSCs). Once these are inserted into the human platform, the landing pad provides a safe place for these intact functioning genes to be integrated into the DNA and their function can be assessed. What does this all mean for AS and why is this delivery system important?

With this research, functional copies of every gene in the entire region can be inserted, or removed, but also combinations of different genes to assess the impact these accompanying genes have on the symptoms of AS can be analyzed. This elegant model allows researchers to consider what other types of therapies might be important after UBE3A replacement or activation is achieved. Long-term outcomes of this research could allow for a better understanding of the overall AS disease pathway, but also additional steps that need to be taken to address symptoms of AS that are not attributed to the loss of UBE3A. These models can also be used to help screen and test promising therapeutics for Angelman syndrome.

Our goal is that this elegant approach will help us to understand the impact these accompanying genes have on the symptoms of AS outside of UBE3A, and allow us to consider if other types of therapies might be needed after UBE3A replacement or activation. This allows for a better understanding of the AS disease pathways and could highlight additional steps we may need to take to address potential remaining symptoms in our deletion population that is not impacted by a loss of UBE3A.

Generation and characterization of a new large deletion AS mouse model

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Before we get into the project and the larger implications for curing AS, let’s talk about animal models. A disease model is typically a non-human model used to mimic the symptoms and mechanism of the condition for research. An example is when engineers build a smaller working model of a building before moving on to creating the actual building itself. In the case of AS, animal models provide opportunities for scientists to better understand the underlying mechanisms of AS and provide insight into a proof-of-concept (POC) for novel treatment options, which must be interpreted carefully, understanding the brain complexities, size, and capabilities of a mouse are nothing like that of a human. Some of the best-known models for AS are the mouse and rat. More recently a pig was created by FAST to be able to assess a “higher” species, closer to a human. Other models are cellular models, like neurons or organoids (mini-brains), which can provide evidence of different types of “read-outs” of disease and are often higher throughput, so faster and cheaper to test to get an early read on promising therapies. All of these models serve an incredible purpose. The animal models can resemble more translatable AS symptoms like cognition, communication, gait, etc, which can give more confidence in the symptoms that may be improved upon with human translation. 

The goal of this project, led by Dr. Jiang, was to create two different mouse models. The first model was created by using genetic engineering to delete not only the ube3a gene but several accompanying genes that are known to be impacted by the large deletion genotype affecting over 70% of the human population living with AS. Another unique addition to this project is creating a second mouse model that keeps the ube3a gene intact while deleting just those additional accompanying genes from the first model. What does this mean for the advancement of potential treatments for AS? Why is this important? Our goal is that this elegant approach will help us to understand the impact these accompanying genes have on the symptoms of AS outside of UBE3A, and allow us to consider what other types of therapies might need to be considered after UBE3A replacement or activation is accomplished. This allows not only for a better understanding of the AS disease pathways but also could highlight additional steps we need to take to address additional symptoms in our deletion population that is not impacted by a loss of UBE3A.

A biorepository of Angelman syndrome human iPSC neuronal cell lines

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The goal of this project led by Dr. Jiang at Yale University is to produce, characterize, and store a biorepository of human AS patient-induced pluripotent neuronal stem cells or iPSCs. Pluripotent stem cells are essentially master, or very early, cells that can make more cells from all three basic body layers. These are the precursor cells because they have not transitioned into specific cell types and they have the ability to self-renew or make more copies of themselves. iPSCs are these types of master cells that can be created from another cell, like blood cells or skin cells from a patient. Then they can be reprogrammed to become neurons. These stem cell lines are essential tools used to screen different therapeutic candidates for AS. Repositories like this one contain all of the different genotypes of AS making, as well as some sibling matched controls, making this a collective location for researchers or industry partners robustly and efficiently test different AS therapeutics. This is a great addition to AS research to ensure cells are able to be used on-demand, and to then understand how therapeutic candidates impact all of the different genotypes of AS.

Outcome measurement assessment for patients with AS (Extended)

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One of the many successful efforts funded by FAST is the development of the first Angelman Syndrome-focused endpoint on communication ability. The Observer-Reported Communication Ability (ORCA) measure was designed to be a sensitive tool to measure receptive, expressive, and pragmatic communication ability in the AS population for use in clinical trials. The ORCA does not rely on speech but allows gestures, vocalizations, and the use of aids to capture communication ability. This current effort extends the previous partnership with Dr. Reeves at Duke University to now take this collected data from ORCA to demonstrate its value in the population. The goal of this project is to inform a “meaningful change” evaluation of the ORCA scores and complete the required supporting documentation to the FDA which demonstrates the value of ORCA for clinical trials. Taking all of the ORCA data and compiling documentation of its value to the AS research community is such an important measure for clinical trials because this allows researchers to detect changes in communication ability over time in a way that is agreeable to the regulatory agencies. Bringing the therapeutics to clinical trials is undoubtedly an important step in treating AS, but having a way to measure if these treatments are improving communication is one of the most important endpoints to parents and caregivers. Currently, this tool is being used in numerous clinical trials in AS, the NHS, as well as being developed for 15 other neurodevelopmental disorders with similar communication challenges as AS.

ABOM-RTI: Accelerating data analysis and publications from Natural History Studies

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FAST and the Angelman Syndrome Biomarker and Outcome Measure (ABOM) Consortium are collaborating with the Research Triangle Institute International (RTI) and Boston Children’s Hospital to accelerate the analysis, correlation, and publication of numerous data sets that have been, and will continue to be, collected on patients through an ongoing Natural History Study (NHS) in Angelman syndrome. The NHS looks to increase our understanding of the long-term natural history of AS and obtain AS-specific norms for outcome measures that can be used in clinical trials with the goal of improving the care and understanding the natural trajectory of functional gains in AS patients. They are working to explore numerous quality of life (QOL) measures for families living with Angelman syndrome which will benefit clinical trial endpoints as well. The data from this study provides insight into key clinical features, medical complications, quality of life impact, and longevity in this population.

Interestingly, some of the correlation studies will evaluate the Bayley Scales of Infant and Toddler Development (BSID), Vineland Adaptive Behavior Scales (VABS), and Observer-Reported Communication Ability (ORCA). To get into what these evaluations are, the BSID is a development tool that assesses cognitive, language, and motor functioning based on a set of standardized tasks. A score is calculated by having an individual complete a set of tasks. VABS serves as a commonly used measure of adaptive behavioral skills for children and adolescents. Lastly, ORCA is a FAST-funded communication tool measuring communication ability in Angelman syndrome specifically, and this is measured by parents and caregivers to assess receptive, expressive, and pragmatic communication abilities. This FAST-funded grant will enable RTI International to expedite the analysis of this robust data in unique ways as additional information to support them as endpoints in clinical trials. This effort will help to support clinical trial design to ensure that the endpoints chosen are sensitive and meaningful to patients and their families.

Adding of AS, Prader-Willi and Dup15Q syndromes to Early Check Newborn Screening Panel

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The Research Triangle Institute (RTI) is working to add Angelman Syndrome, Dup15p, and Prader-Willi Syndrome to the Early Check Newborn Screening Panel. The Early Check Newborn Screening Panel tests for a small number of serious health conditions in newborns free of charge. This panel collects information in the hopes to show the benefits of early detection, testing, and treatment to improve the larger Newborn Screening across the US. Adding AS to this panel would allow parents to find out about an AS diagnosis within weeks of birth and before any symptoms appear. AS is not currently part of the larger Newborn Screening panel in the US and so adding it and these other conditions would allow data to be gathered in favor of making the push to have them included in the US standard screening program and to better understand the true incidence of this disorder. This effort is jointly funded by FAST, the Dup15p Foundation, the Prader-Willi Syndrome Research Foundation, and the Angelman Syndrome Foundation.

Isogenically controlled human cell lines targeting aberrant imprinting genotypes and a new reporter cell line

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Dr. Keung from NC State is currently working on a project to create two types of human stem cell lines – a group of cells that all descend from a single original stem cell and are grown in a lab that resembles the paternal imprinting patterns similarly seen in the imprinting center defect (IPD) and uniparental disomy (UPD) genotypes of AS. For UPD (~3-5% of AS patients) two copies of chromosome 15 are inherited from the father (instead of one from each parent) and for ICD (~3-5% of AS patients) there is a defect at the imprinting center on the maternal allele, which prevents the normally active maternal copy of UBE3A from being turned on. These are two of the more rare forms of AS. Since many of the AS therapeutics target activation of the paternal allele, this questions the impact that could have when there are 2 paternally silenced copies in this population.

Expedite: Accelerate promising research toward clinical trials, approvals and global patient access, through robust parallel funding strategies from pre-clinical drug screening to discovery of human drug candidates, while simultaneously advancing all aspects of clinical trial readiness.

FAST Infrastructure

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Drs. Segal, Silverman, and Fink from UC Davis are working on a project to enable the rapid testing of potential AS therapeutics in cell, tissue, and animal models of AS. The FAST Infrastructure grant aims at minimizing the time required for the start-up of new projects that will be testing new AS therapeutic candidates by different partners (academic or industry) to have to breed AS colonies of animals, learn and understand the symptoms of those animals and then test their compound in these models. By utilizing an existing colony with people that are experts in neurobehavior and AS biology, this program maximizes the efficiency across multiple AS projects and supports several academic and industry partners working in the AS field. This infrastructure provides essential laboratory equipment, rodent breeding/housing, and research personnel with expertise in molecular and behavioral analyses essential to studying AS. This program shortens the time needed to acquire these important tools speeding up the timeline for testing these therapeutics and allowing for promising candidates to be tested by neurobehavioral experts. To date, this program has successfully accelerated numerous therapeutic candidates through proof-of-concept phases and is continuing to do so.

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IND Enabling studies for HSC therapy in AS

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Dr. Joe Anderson from UC Davis is currently working on a project of hematopoietic stem cell (HSCs) gene therapy that was developed for AS through the original grant-funded by FAST in 2016. What are HSCs? HSCs are early blood stem cells that are in the bone marrow and travel around the circulation that can give rise to all the different types of blood cells through differentiation in the bone marrow. These blood cells are currently being researched to deliver an AS therapeutic because these immature cells make all of the blood cells that circulate in the blood vessels around the entire body and can even cross the blood-brain barrier and get into the brain. These cells could be present in the patient for their entire lives. This means that a potential treatment could be delivered to all of the affected cells in a patient’s body. These additional studies are being performed to support accelerating this gene therapy platform toward the requirements needed by the regulatory agencies to apply for a potential clinical trial.

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