What does the R in our C.U.R.E-AS funding philosophy stand for?
What does the R in our C.U.R.E-AS funding philosophy stand for?

💡 Ready: FAST is committed to establishing and maintaining 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. Keep reading to learn more about the eight grants that have been funded under FAST’s C.U.R.E-AS philosophy. 👇

🏥 GRANT: Translational Research in Pig Model of AS: Watch

Texas A&M University is in the process of characterizing an Angelman syndrome (AS) pig model. The current pig model was established under another FAST-funded effort. Now, Dr. Dindot is striving to develop, test and validate potential therapies for AS. Dr. Dindot will be using this model to assess any behavior changes following the activation of the paternal copy of the UBE3A gene or replacing the material copy. Pigs are incredibly smart animals with anatomy and physiology more similar to humans, compared to the numerous rodent models available. The AS pig model can showcase AS symptoms, such as cognition, communication, gait, seizures and others, which can and will be evaluated in this research effort. Animal models continue to provide opportunities for scientists to better understand the underlying mechanism of AS. 

🏥 GRANT: Human platform to efficiently study Class 1 Deleted Genes: Watch

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. Understanding their impact on the symptoms of AS, outside of UBE3A can drive the need for additional therapeutics for this population of patients. Dr. Keung from NC State is currently working on a human platform to study these deleted genes efficiently. 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. 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 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 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, and combinations of different genes to assess the impact of these accompanying genes on AS symptoms can be analyzed. This elegant model allows researchers to consider what other 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 attributed to the loss of UBE3A. These models can also be used to help screen and test promising therapeutics for Angelman syndrome. 

🏥 GRANT: Generation and characterization of a new large deletion AS mouse model: Watch

This project, led by Dr. Jiang, was outlined to establish 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 a better understanding of the AS disease pathways and 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. 

🏥 GRANT: A biorepository of Angelman syndrome human iPSC neuronal cell lines: Watch

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 and 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 from a patient. They can be reprogrammed to become neurons. The 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 and some sibling matched controls, making this a collective location for researchers or industry partners robustly and efficiently test different AS therapeutics. This is an excellent addition to AS research to ensure cells can be used on-demand and to understand how therapeutic candidates impact all of the different genotypes of AS. 

🏥 GRANT: Outcome measurement assessment for patients with AS (Extended) Watch

This effort extends a previous FAST-funded effort and partnership with Dr. Bryce Reeves to develop 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 aids to capture communication ability. This current effort extends the previous partnership with Dr. Reeves at Duke University to take the 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. Outlining the ORCA data and compiling documentation of its value to the AS research community is an important measure for clinical trials. 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 and is being developed for 15 other neurodevelopmental disorders with similar communication challenges as AS. 

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

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 in Angelman syndrome. The data from the NHS provided insight into key clinical features, medical complications, quality of life impact, and longevity in this population. These correlation studies will evaluate the Bayley Scales of Infant and Toddler Development (BSID), Vineland Adaptive Behavior Scales (VABS), and ORCA. In addition, the team will work to explore numerous quality of life (QOL) measures for families living with Angelman syndrome, which will also benefit clinical trial endpoints. The FAST-funded grant will enable RTI International to expedite the analysis of this robust data in unique ways as additional information and endpoints are added to the study and support clinical trial design to ensure that the endpoints chosen are sensitive meaningful to patients and their families. 

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

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. The panel collects information in the hopes of showing the benefits of early detection, testing, and treatment to improve the larger Newborn Screening across the US. Adding AS to the 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. The effort is jointly funded by FAST, the Dup15p Foundation, the Prader-Willi Syndrome Research Foundation, and the Angelman Syndrome Foundation. 

🏥 GRANT: Isogenically controlled human cell lines targeting aberrant imprinting genotypes and a new reporter cell line. Watch

This study, led by Dr. Keung, aims to generate two types of human stem cell lines that resemble paternal imprinting patterns similar to that in the ICD and UPD genotypes of Angelman syndrome. The goal of this work is to provide human stem cell lines that can be shared and rapidly used by other investigators and industry partners. These can be used to explore various therapeutic platforms specifically in these rarer genotypes, and understand the changes in phenotype, or neuronal behavior, compared to the other more common genotypes known to be associated with AS. In addition, this system will also facilitate the study of mosaic forms of Angelman syndrome.