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Here is what our FAST community’s donations have funded:
Collaborate: FAST is committed to 360-degree collaborations, including numerous routes where FAST collaborates with industry, academic partners, other national and global organizations, and government professionals to advance the drug development pipeline for Angelman syndrome. FAST can ensure that progress is made toward the mission to find effective and transformative therapeutics for all individuals living with Angelman syndrome (AS).
The Emergency Care Consortium is a FAST-funded multiple-year contract aiming to provide services in emergency and urgent situations for patients living with AS. The consortium is available 24 hours a day, days a week and can be reached at 1-800-525-4871 and AngelmanExpertConsult @childrenscolorado.org. The Emergency Care Consortium aims to ensure that all patients around the world living with AS get the best medical care possible. By calling the number, families are provided with a formal process that connects the patients’ local medical providers to experts familiar with AS management and current protocols – particularly in emergency situations relating to seizures.
Understand: FAST is committed to investigating, identifying and funding research opportunities leading to numerous human therapeutic candidates. FAST is committed to establishing an infrastructure to support pre-clinical work which could potentially lead to human benefit.
Many in the AS community are very familiar with that AS 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.
Ready: FAST is establishing and maintaining an enduring framework to provide the most robust animal models and cell lines for testing. FAST is ensuring that clinical endpoints and biomarkers are sensitive and meaningful for patients with AS, all therapeutics are tested in de-risked for all genotypes, and clinical trial readiness is maximized.
Dr. Dindot at Texas A&M University is actively characterizing an AS pig model. The current pig model was established under another FAST-funded effort. The next step forward is striving to develop, test, and validate potential therapies for AS using this novel model. Dr. Dindot will be using this model to assess behavioral changes seen after either activating the paternal copy or replacing the material copy of the UBE3A gene. Pigs are incredibly advanced animals with anatomy, physiology and neurobehavioral assessments more similar to that described in humans compared to the numerous rodent models available. The AS pig model has far more comparable AS symptoms, like cognition, communication, gait, seizures and others than any other model. This can more accurately help predict phenotypic rescue with various different drug candidates for AS.
Nearly 70% of individuals with AS have a large deletion on the maternal copy of chromosome 15, encompassing the UBE3A gene and including an additional number of genes outside of UBE3A. These are an important set of genes to study since they are impacted in such a large percentage of AS patients. 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 at NC State is currently working on a human platform to efficiently study these deleted genes. This project aims to create a human platform, or human model, that can be used to study the deletion of UBE3A and the surrounding genes. By creating this novel ‘landing pad’, gene combinations can be added to assess the specific function, or loss of function, when different genes are removed or added after UBE3A is replaced.
With this research, functional copies of every gene in the entire region can be inserted, removed, and combined with different genes to assess the impact these accompanying genes have on the symptoms of AS. 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 and additional steps that need to be taken to address symptoms of AS that are not only attributed to the loss of UBE3A. These models can be used to help test other promising therapeutics for AS that impact these additional genes.
FAST’s goal is that this novel approach will help to understand the impact these accompanying genes have on the AS symptoms outside of UBE3A and allow consideration of other types of therapies that might be needed after UBE3A replacement or activation. This allows for a better understanding of the AS disease pathways and could highlight additional steps necessary to address the potentially remaining symptoms in the AS deletion population that is not impacted by a loss of UBE3A.
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 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 give insight into a proof-of-concept (POC) for novel treatment options, which must be interpreted carefully. The understanding of the brain complexities, size and capabilities of a mouse are nothing like that of a human, therefore we interpret this information carefully, while using the information as a proof-of-concept. Some of the best-known models for AS are the mouse and rat. More recently, a pig model was created through the support of FAST to enable assessment of a more complex 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. They are often higher throughput, meaning faster and cheaper to test to get an early read on promising therapies. These models serve an incredible purpose. The animal models can resemble more translatable AS symptoms like cognition, communication, gait and others, which can give some confidence in the symptoms that may be improved upon with human translation.
The project, led by Dr. Jiang, was established 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 human patients living with AS. A 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. FAST’s goal is that this innovative approach will help to understand the impact these accompanying genes have on the symptoms of AS outside of UBE3A. It will allow the scientific community the opportunity to consider what other types of therapies might need to be considered after UBE3A replacement or activation is accomplished. This allows for a better understanding of the AS disease pathways. It could also highlight additional steps necessary to address other symptoms in our deletion population that are not impacted by a loss of UBE3A.
This project led by Dr. Jiang at Yale University aims 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. They can self-renew or make more copies of themselves. iPSCs are master cells that can be created from another cell, like blood cells or skin cells of a patient. 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 the different genotypes of AS and some sibling matched controls to make these lines available for both researchers and industry partners to test different AS therapeutics robustly and efficiently. This is a great addition to AS research to ensure cells can be used on-demand and then understand how therapeutic candidates impact all the different genotypes of AS.
One of the many successful efforts funded by FAST is the development of the first AS-focused endpoint on communication ability. The Observer-Reported Communication Ability (ORCA) measure is a sensitive tool to measure receptive, expressive and pragmatic communication ability in the AS population for use in clinical trials. 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 take this collected data from ORCA to demonstrate its value in the population. This project aims 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 the ORCA data and compiling documentation of its value to the AS research community is an important measure for clinical trials because it allows researchers to detect changes in communication ability over time in a way that is agreeable to the regulatory agencies. Bringing 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, Natural History Study (NHS,) and is being developed for 15 other neurodevelopmental disorders with similar communication challenges as AS.
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 AS. The NHS looks to increase the understanding of the long-term natural history of AS and obtain AS-specific norms for outcome measures that can be used in clinical trials to improve the care and understand the natural trajectory of functional gains in AS patients. Additionally, this team is working to explore numerous quality of life (QOL) measures for families living with AS, which will benefit clinical trial endpoints. 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). 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. ORCA is a FAST-funded communication tool measuring communication ability in AS specifically. This is measured by parents and caregivers to assess receptive, expressive, and pragmatic communication abilities. This 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.
The Research Triangle International (RTI) is working to add Angelman syndrome, Dup15q 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 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 know 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. These data will help to make the push to have AS 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 Dup15q Foundation, the Prader-Willi Syndrome Research Foundation and the Angelman Syndrome Foundation.
Dr. Keung at NC State University is currently working on a project to create two types of human stem cell lines. This team is creating a group of stem cells originating from the patient lines that are part of the FAST-funded Yale University biorepository. The project aims to resemble paternal imprinting patterns of imprinting center defect (ICD) and uniparental disomy (UPD) genotypes of AS. UPD, which affects ~3-5% of AS patients, has two copies of chromosome 15 inherited from the father, instead of one from each parent. ICD, which affects ~3-5% of AS patients, has a defect at the imprinting center on the maternal allele, which prevents the normally active maternal copy of UBE3A from turning on, creating two silent copies, like UPD. These are two of the rarer forms of AS. Since many of the AS therapeutics target activation of the paternal allele, this questions the impact that these drugs could have when there are two paternally silenced copies in this population, and both are activated.
Expedite: FAST is accelerating promising research toward clinical trials with the goal of eventual therapeutic approvals and global patient access. This is done 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.
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 test their compounds in these models. By utilizing an existing animal colony that are being tested by these experts in neurobehavior and AS biology, this program maximizes the efficiency across multiple AS projects. It 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 important tools, speeding up the timeline for testing these therapeutics and allowing for promising candidates to be tested by neurobehavioral experts.
Dr. Joe Anderson from UC Davis is currently working on a project of hematopoietic stem cell (HSCs) gene therapy. It was developed for AS through the original grant-funded by FAST in 2016. HSCs are early blood stem cells in the bone marrow that travel throughout the circulation, giving rise to various types of blood cells through differentiation within the bone marrow. These blood cells are currently being researched to deliver a modified UBE3A gene therapy where they can cross the blood-brain barrier, get into the brain, and deliver the needed UBE3A. These cells could then be present in the patient for their entire lives. This means that a potential treatment with UBE3A could be delivered throughout the brain. 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.