2025 FAST Global Science Summit Recap

Speaker: Michael Boland, PhD, University of Pennsylvania Perelman School of Medicine

Watch the full presentation here.

Summary: In vitro experiments take place in an environment outside of a living organism (test tube, petri dish, cell culture flask) and are critical for understanding disease mechanisms. For drug discovery, in vitro experiments are used to determine how a potential drug interacts with its target and gives an early indication of how cells tolerate the drugs presence. What is commonly used in Angelman syndrome or stem cells created from human blood samples that are manipulated in a laboratory into human neurons that have Angelman syndrome. Then the neurons can be tested for function in a dish before and after different drugs are tested on them. In addition to neurons, organoids, 3-dimensional models of an organ that are grown from stem cells, can sometimes reproduce key features of the organ of interest. Organoids made up of the cells found in the human brain, or cerebral cortex, can be used to test different therapies such as a gene therapy, and ASO, or a gene editor (CRISPR), and see if that is able to correct the defective gene. These experiments are generally the first step in drug discovery.

Speaker: Rodney Samaco, PhD, Rare Collective Strategies LLC

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Summary: In vivo experiments take place in a living organism, generally rodents (mouse or rat) which have been genetically altered to display the phenotypes, or symptoms, of a disease. For AS, the mouse model has been used to understand the function of Ube3a and how it is regulated. These types of experiments have led to the development of many different novel therapies. The AS mouse model has been used to understand the potential outcomes of many therapeutic strategies, which is a key step in the drug discovery process.

Emerging human data from clinical trials can be compared with what was observed in the AS mouse model of a similar type of therapy. These comparisons will allow for better understanding of how the AS mouse can be best used to translate to might be expected in humans, which will further enable understanding the most efficient way to advance the development of AS therapeutics.

Speaker: Seth Margolis, PhD, Johns Hopkins University School of Medicine

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Summary: Neurons need a way to direct proteins to ensure the balance in the cell is appropriate, which helps to ensure healthy function. This can be done by signaling a protein to be broken down, upregulated, or “directed” in different ways. In cells, like neurons, there is something called the proteosome, which is a cellular complex that helps to break down and recycle unwanted proteins. In order for the proteosome to know if a protein is ready for breakdown, the protein must be tagged. One class of proteins that does this tagging is called E3 Ligases. UBE3A is one of 600 E3 Ligases. When UBE3A is absent, the proteins that were meant to be tagged can build up causing a cell to malfunction. By understanding this mechanism as a function of the missing protein, UBE3A, in AS, the possibilities of different targets and approaches to consider addressing the and improving the UBE3A function at a cellular level are highlighted.

Speaker: Emma James, DPhil, Encoded Therapeutics

Watchful presentation here.

Summary: Gene therapy is a treatment that addresses the root cause of a genetic disease, like Angelman syndrome. Gene therapy is a “blanket term” for many therapeutic approaches that alter the way a cell works. DNA gene therapies deliver a corrected gene to the cells that are missing the functional gene copy. RNA gene therapies modify how a specific disease-causing protein is made or regulated, so the defective or missing protein that is the cause of the disease is replaced with a functional protein. Cell-modification therapies modify the patient’s own cells outside their body using DNA correction techniques, then the corrected cells are returned to the patient and allowed to grow (e.g. ex-vivo hematopoietic gene therapy). The objective of each of these therapies is to replace the defective or missing protein that is the cause of a disease with one that is functional.

There are multiple gene therapies available to treat specific diseases, and techniques are constantly being developed to improve them. These improvements include more efficient delivery of DNA therapies to the cells of interest, increasing the half-life of RNA therapies so they can be delivered less often, and improving the efficiency of cell-modification therapies to allow for the best outcome. Many different types of gene or RNA-targeted therapies are being developed for Angelman syndrome including: AAV-Gene Replacement Therapy, HSC-Gene Replacement Therapy, CRISPR gene editing, Antisense oligonucleotides (ASO), Artificial Transcription Factors (ATFs), miRNA/shRNA, and siRNA.

Speaker: Allyson Berent, DVM, DACVIM, FAST and AS²Bio

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Summary: Angelman syndrome is a monogenic, non-degenerative neurologic disorder, that is caused by the loss or significant reduction in expression of the UBE3A gene, which is located on chromosome 15. UBE3A is an imprinted gene, meaning that while everyone inherits two copies of the gene (one from each parent), only one is expressed. In the case of UBE3A, the gene is expressed from the maternal copy, while the paternal copy is silenced. If the mother’s copy of this imprinted gene is missing or damaged, there is no alternative copy that can be expressed in the cells it is silenced in. AS is caused by a missing or damaged maternal copy of UBE3A, which leads to an absense in the UBE3A protein in brain cells, called neurons. 60-80% of individuals with AS have a type of AS called a “deletion” where they are missing a segment of maternal DNA including this UBE3A gene. In addition, 10-15% of AS individuals have a “mutation” where within the maternal UBE3A gene the code is disrupted (wrong letter, missing letters or added letters) impacting the function or expression of this gene. Another 3-10% of AS individuals have uniparental disomy (UPD), and 3-6% of AS individuals have an imprinting center defect (ICD), and with these genotypes both the alleles (copies) of UBE3A are silenced, or imprinted. Finally, about 1-3% of AS individuals have something called mosaicism, where a majority of their cells don’t express maternal UBE3A, but a small amount do, and they have more mild symptoms than the others. While loss of UBE3A expression or function is the primary driver of most of the symptoms seen in AS, individuals with the deletion type of AS are also missing several other genes surrounding UBE3A, and some of these likely play a role in some of the increased severity of symptoms (e.g. seizures, motor function, etc.). Despite the genotype, or type of AS a person is experiencing, the symptoms are all very similar, showing the importance of the common missing or nonfunctional gene of UBE3A. The clinical symptoms of AS include a near-universal lack of speech, severe sleep challenges, seizures, incoordination and balance challenges, gastrointestinal issues, and impulsivity/self-directed behaviors. Currently, those living with AS are unable to live independently, and there is a substantial clinical unmet need. AS also dramatically impacts families and caregivers, causing stress, social isolation, difficulty with sleep resulting in chronic fatigue, as well as resulting in a significant financial hardship. There are currently no approved therapies that directly treat AS, so we are working very hard to change that and change the trajectory of development for those living with AS. Due to understanding the genetic basis of AS, and the fact that those with mosaicism who have as little as 1-5% of cells expressing maternal UBE3A, There is strong reason to believe that AS an ideal target for the development of therapies that can replace the missing UBE3A gene or protein. FAST’s 5 pillars of drug development constitute a roadmap for achieving the goal of discovering disease-modifying therapies for AS that could have the greatest possible impact. The 5 pillars are:

1. Replace mom’s UBE3A: Gene replacement therapy can be accomplished in multiple ways, including by using AAV viral vector, an enzyme replacement therapy (ERT), or by modifying the patient’s own blood stem cells to make functional UBE3A (HSC-GT). AAV-GT and Hematopoietic stem cell gene therapy (HSC-GT) has been shown in AS mice to result in robust and widespread expression of the UBE3A protein throughout the brain and treated animals show significant improvements in numerous different assessments, giving potential for benefit with these technologies. The first gene therapy, using an AAV, is currently in a phase 1/2 clinical trial for Angelman syndrome.

2. Turn on dad’s UBE3A: Activating the paternal copy of UBE3A by unsilencing the paternal UBE3A- antisense transcript (UBE3A-ATS) can be done using many different technologies including: antisense oligonucleotides (ASOs), artificial transcription factors (ATFs, zinc fingers), CRISPR gene editing, miRNA and siRNA. These technologies are currently in development for AS with 3 different ASO programs in clinical trials.

3. Exploring adjacent genes: AS individuals with the deletion genotype are missing additional adjacent genes to UBE3A. CRISPR activation, a technology that can upregulate a gene to express more, may be able to increase the expression of these missing genes, which are present on the fathers (paternal) copy. Only the UBE3A is silenced on the fathers copy but not these deleted adjacent genes. Experiments in human neurons and AS mice with similar deletion to that of people are ongoing to test this approach as a potential full strategy for the deletion group. For UPD/ICD, experiments are ongoing to understand the specific impact of overexpression or under expression of these additional genes and RNA and trying to further understand some unique mutations that might have a gain of function or dominant negative effect, rather than a loss of function as seen in most mutations, is ongoing. Better understanding of this will help to drive options like base and prime editing to best address the specific mutation on the maternal copy and restore UBE3A.

4. Targeting downstream pathways: Compounds that treat specific symptoms of AS have the potential to be beneficial either alone, or in combination with therapies from pillar 1-3. Treating the results of a missing UBE3A, which results in communication between neurons being abnormal, or a synaptopathy, can help to better regulate learning and memory and neuronal fuction. Some examples are through different pathways like the BDNF pathway and GABAergic signaling. Alogabat, a compound that restores GABAergic signaling, is currently in a phase 1/2 clinical trial with AS patients.

5. Preparing for clinical trials and patient access: There have been significant efforts to support the development of innovative therapies, including the development of multiple AS animal models, the establishment of the International Angelman Syndrome Research Council (INSYNC-AS), the establishment of the Angelman syndrome Biomarker and Outcome Measure Consortium (A-BOM), and support of the NIH-funded AS natural history study, which has collected data from over 600 AS individuals worldwide. FAST has supported patient advocacy efforts, as well as the Global AS Registry, and we continue to work on newborn screening efforts for AS. In 2025, FAST and ASF brought families to Congress to educate lawmakers on AS, and in April of 2025, FAST and ASF hosted a patient-focused drug discovery meeting (PFDD) with the FDA, during which families and caregivers of AS individuals could share their experiences directly with regulators about what is meaningful and important to them and what a meaningful change could look like for a drug program. The outcome of the PFDD meeting has been published and is available as a resource for anyone working on drug discovery for AS (https://angelmanadvocates.org/voice-of-patient-report).

Establishment of the A-BOM is critical for helping companies interested in developing therapies for AS to truly understand what measures are available, what measures capture meaningful change, and where there are gaps to design our own measures for clinical trial use. FAST has contributed over 5 million dollars on work in this area in a pre-competitive manner, and this is all used to help inform anyone working in AS to help design the best possible clinical trials.

FAST’s primary goal is to have multiple effective treatment options available for every person who wants one living with AS. FAST has used their resources to fund programs that have promise as therapies, and even though the landscape of drug development is often volatile and has ups and downs. Today there are multiple therapeutic programs targeting AS, some of which are sitting on a shelf due to priority shifts at drug companies. But most of these programs that have promising early pre-clinical data are moving closer to human application. FAST is committed to doing everything possible to keep moving therapies for AS forward, and will continue to identify gaps, fund promising science, and support any therapy that can have a positive impact on individuals living with AS.

Today there are 30 programs in development for AS, some of which are not yet disclosed publicly. There is 1 gene therapy, 3 ASOs, and 2 small molecular in clinical trials. We expect 2 additional gene targeted therapies to reach clinical trials soon! What is truly incredible is that FAST funding has supported, or continues to support, 16 of these programs, and 4 of the 8 that are in IND-enabling or clinical trials! This is the power of patient advocacy.

Speakers: Jennifer Panagoulias, RAC, FAST and AS²Bio, COO, Allyson Berent, DVM, DACVIM, FAST and S²Bio

Watch full presentation here.

Summary: The Angelman Syndrome Biomarker and Outcome Measure Consortium (A-BOM) is a precompetitive consortium where stakeholders can work to establish a consensus on optimal outcome measures for each functional domain. A-BOM also seeks to engage with regulators to ensure alignment and agreement on outcome measures, and when necessary, develop novel measures to fully capture the experience of patients and families living with AS. The outcome of ABOM’s work is the establishment of a framework to support clinical trial design, with freely available and accessible outcome measures and biomarkers for anyone to use in order to truly help identify drug that improve lives.

The A-BOM meeting took place in a closed door setting with sponsors, regulators, researchers and clinicians present to talk deeply about how to best measure change in the clinical symptoms that matter most to families in a clinical trial setting. Highlights from the meeting:

• Discussion on the parent perspective of benefit/risk for a gene therapy in AS, including insights from caregiver focus groups on perceived risk/benefit and willingness to participate in clinical trials.

• Discussion of ORCA scores, what they mean, and how they can be interpreted, including feedback from caregivers on a survey to help establish the meaning of a score change if the impact that score can have on daily life.

• Discussion of challenging behaviors in AS, including understanding behaviors beyond the concept of “anxiety” and how these behaviors impact families based on the EL-PFDD meeting and with feedback from Michele Campbell at the FDA on how challenging behaviors in individuals with neurodevelopmental disorders, like AS, might be used as potential endpoints in clinical trials. We learned about the endpoints like the ABC-C and the ASA in the behavior domain and how this is moving in the current ASO clinical trials.

• In addition, there was discussion on sleep and cognition and the impact those domains have on caregivers and how we can best measure change in a clinical trial setting.

The Translational Research Symposium (TRS) aims to create an environment where cutting edge discovery can be shared with a community of researchers, clinicians, and industry representatives. The goal of the symposium is to provide a forum for discussion and collaboration that both supports new and novel ideas, and shares failures and setbacks, to avoid repetition and share resources.

Highlights from the TRS portion of the meeting:

• Presentations on novel therapeutic approaches for AS, including CRISPR-Cas13 as a gene editing strategy, and ATF-Zinc fingers for paternal UBE3A activation.

• Discussion of the importance of specific genes outside UBE3A in deletion genotypes.

• Measuring UBE3A function, and measuring the amount of UBE3A in CSF, and how those measurements can help us understand if therapies are working.

• UBE3A and its role in autophagy, and how that might help us understand brain health and neuronal function.

Speaker: Jennifer Panagoulias, RAC, FAST and AS²Bio, COO

Watch full presentation here.

Summary: Biomarkers are measurable physical properties of the body that may change when the body is under stress or in response to a disease. Examples of biomarkers that can be monitored include changes in blood chemistry, CSF composition, MRI scans, and EEG recordings. Outcome measures are tools to assess the way a patient feels, functions, or survives, and ideally captures what matters most to patients or caregivers. Both biomarkers and outcome measures can be utilized as endpoints in a clinical trial. An endpoint is a targeted outcome of a clinical trial that can be statistically analyzed to determine the safety and efficacy of the therapy being evaluated. Biomarkers can sometimes be used as endpoints for clinical trials when they can be demonstrated to predict clinical benefits. When a biomarker is used in this way, it is referred to as a surrogate endpoint. Surrogate endpoints are used when an outcome measure takes a long time to study, such as loss of walking ability in a neuromuscular disease, or when the correlation between the biomarker and the outcome is very well understood, such as reduction of blood pressure reducing the risk of stroke.

Having robust biomarkers can enable faster and more efficient clinical trials which can result in therapies being brought to patients sooner, when there is a clear signal that something is changing. In AS, several potential biomarkers are being evaluated, including EEG delta power, MRI, and measuring UBE3A and other markers in CSF. Currently none of these biomarkers are being used as endpoints in any AS trials, however, work is ongoing to gather the data to allow them to be used in future trials.

Speaker: Yong-Hui Jiang, MD, PhD, Yale University

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Looking Ahead: The AS neurons available in the repository can also be used to generate human organoids which recreate key elements of the human brain. These organoids are being used to test various therapeutic strategies, like the STEP-RNP gene editing program.

Summary: Having a human cell line that can be used to test potential therapies provides critical information about how a therapy will impact human neurons. Following an established protocol, cells in blood donated by a person can be extracted and turned into neurons. This is done by taking different steps to create induced pluripotent stem cells (iPSC), a type of stem cell that can be reprogrammed to form any type of cell, including neurons. Cultures of these iPSC derived AS neurons can be used to screen and test novel therapies that can impact neurons.

Because of the importance of iPSCs to AS research, a repository of iPSC cells has been created, which includes cells from AS patients with different genotypes. The repository currently includes 4 cell lines from individuals with large deletions (maternal deficiency of 15q11.2-q13.1), 4 cell lines from individuals with UBE3A mutations resulting in maternal loss of function, 4 cell lines from individuals with uniparental disomy, and 3 cell lines from individuals with imprinting center defects. The repository also includes 6 cell lines from individuals who do not have AS. These cells are stored at the European Bank for induced pluripotent Stem Cells (EBiSC) and are available to any interested researchers.

Speaker: Xiaona Lu, MD, PhD, Yale University

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Looking Ahead: The ASLD mouse model is available for researchers to use in AS research or therapeutic development and can serve as a strong model when considering treatment effect for the larger deletion population and the impact of the genes outside of Ube3a.

Summary: The most commonly used AS mouse model was created by deleting a portion of the Ube3a gene from the maternal allele, resulting in non-functional Ube3a (Ube3a knockout) in neurons, but leaving the rest of the genome intact. This mouse does not completely represent the most common genotype of AS, in which a large segment of chromosome 15 is deleted. The Angelman syndrome large deletion mouse (ASLD) has a 6MB chromosomal deletion (15q11-q13), similar to a human Class 1 deletion. The ASLD mice exhibit more frequent seizure-like events and disrupted sleep patterns when compared to the traditional Ube3a only knockout mice. The delta power on an EEG were higher than either the traditional Ube3a knockout or wild type mice. The ASLD mice also showed reduced alpha, sigma, and beta activity in EEG relative to Ube3a knockout or wild type mice.

The ASLD mice have been treated with the STEP RNP gene therapy. Treatment on day 1 post-birth (neonate) or day 21 (juvenile) post-birth improved most of the neurobehavioral phenotypes, and in addition reduced seizure susceptibility and rescued the fragmented sleep patterns. ASLD mice treated with STEP RNP also showed a rescue of the increased delta power observed in untreated ASLD mice, and increased alpha, beta, and sigma activity relative to untreated ASLD mice.

Speaker: Nadav Ahituv, PhD, University of California, San Francisco

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Summary: CRISPR activation targets a genes regulatory element to upregulate expression of that gene. This strategy can be used when there is too little gene expression (haploinsufficiency) of a gene, as is the case for the genes outside of UBE3A in the deletion genotype. In AS, individuals with the deletion genotype are missing half the function of other genes adjacent to UBE3A. CRISPR activation can be used to upregulate expression of the other genes that are found to be important in AS. Five other genes are being evaluated for their contribution and they will each be tested individually and together in AS neurons and the ASLD mouse model.

Constructs for each gene have been optimized for use in human cells, the mouse version to be used in mouse models.

Speaker: Wayne Chadwick, PhD, Healx

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Looking Ahead: Work on improving the physical properties of HLX-B and HLX-C are underway, with the objective of beginning a clinical trial in 2026 with one of the lead compounds.

Summary: Healx uses an AI-driven platform to discover both novel mechanisms and novel therapeutics for rare diseases. For AS, the algorithm identified 6 potential candidates. An in vitro screen with a library of additional compounds with similar properties as the 6 initial candidates identified a set of potential candidate compounds. The small set of compounds were tested in neurons derived from AS mice, and the two which performed the best were advanced to testing for rescue of function in AS mice.

Both compounds identified in the in vitro screen (HLX-B, HLX-C) improved AS mice performance on the rotarod, open field, and marble burying tests, indicating the compounds had a positive impact on motor coordination and motor control.

Speaker: Sarah Nelson Potter, PhD, CCC-SLP, RTI International

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Looking Ahead: Questions needing to be addressed include how various factors (e.g. caregiver education, family income) influence the development of adaptive skills in AS individuals.

Summary: Adaptive behavior is a term that describes the everyday skills that people need to live independently. Changes in an individual's ability to perform these skills before and after treatment are frequently assessed during the development of new therapeutics. Individuals with AS show deficits in many adaptive behaviors, which substantially impacts their quality of life. Using the Vineland adaptive behavior scales 3rd edition (Vineland-3) changes in adaptive function over time in individuals with AS were evaluated. In addition, changes in adaptive function with time in individuals with different AS molecular subtypes were examined.

Analysis of Vineland-3 data measured multiple times in 331 individuals with AS indicated that non-deletion AS individuals generally show a higher level of skills compared to deletion AS individuals. Most rapid progress for all AS individuals occurs early in life and slows as the individual ages for all genotypes. However, individuals with AS demonstrate some growth in all adaptive domains regardless of age or genotype.

Speakers: Anne C. Wheeler, PhD, RTI International, Anjali Sadhwani, PhD, Boston Children’s Hospital

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Summary: Clinical outcome assessments are critical for understanding if a drug is working, and improper or inconsistent collection of outcome assessments may result in a drug failing in clinical trials, even if it works. The Bayley and Vineland assessments are 2 of the most frequently used outcome measures in clinical trials for AS. Consistent application of these assessments is important for collecting reliable data. For the Bayley assessment, parents can help ensure consistency by familiarizing themselves with the assessments and what they mean. In addition, parents can try to ensure their children are well-rested, feeling like themselves, and enthusiastic about the test, as well as informing the testers about any potential factors which may impact performance (lack of sleep, new medication, etc.). The same parent should be with their child each time the assessment is done and work with the rater to ensure the motivation is consistent to ensure best performance each time. For the Vineland assessment, parents can ensure consistency by making sure they have the appropriate time to focus on answering the questions, as well as answering questions as honestly as possible, while considering their child’s behavior in different settings, and by using specific examples. Again, the same caregiver should be the one to answer the questions on the Vineland each time.

A set of Do’s and Don’ts has been assembled for parents to help them prepare themselves and their children for Bayley and Vineland assessments. These guidelines will help ensure that the data collected is of high quality, consistent and reflective of their child’s functional abilities.

Speaker: Kimberly Goodspeed, MD, Ultragenyx

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Looking Ahead: The MDRI will be used in the GTX-102 Phase 3 study, and the data collected in the Phase 1/2 study will be further analyzed.

Summary: Selecting a single primary endpoint in a clinical trial with a disorder like AS can be a challenge because symptoms and their severity may vary from person to person. A drug may help many individuals with AS in different ways, but a single endpoint would only capture the patients that benefit in the way the endpoint specifies, which may lead to a drug failing even though it is beneficial to patients in other focus areas. The Multi-domain Responder index (MDRI) captures improvements across multiple independent symptom domains, to quantify the effects of a treatment on multiple symptoms that matter to patients and families, instead of relying on a single symptom. This means that gains and losses across multiple measures can be accounted for, leading to a more complete picture of the different drug effects.

To develop the MDRI framework in AS, Ultragenyx picked 4-6 clinical symptoms that were of specific importance to the AS community, and meaningful changes in those symptoms were defined and given a numerical score. For each patient, the scores across all the symptoms measured were added up and subjected to statistical analysis to define which participants demonstrated meaningful change with treatment in that domain. The MDRI was used in the GTX-102 Phase 1/2 clinical trial and showed that 79% of patients had meaningful improvement with treatment across domains.

Speaker: Abigail Rader, Duke University

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Looking Ahead: Creating score regions that describe similar levels of ability. Utilizing the vignettes to help family caregivers understand what a change in ORCA score may mean to the daily life of the family.

Summary: The Observer-Reported Communication Ability (ORCA) measure was developed specifically for AS and uses rigorous methods to generate a score in communication ability that more completely describes that in a person with AS. However, the score alone does not adequately convey what a child’s communication ability is, or how it compares to similarly aged AS individuals, nor does it indicate what an improved score means. Putting the scores in context allows for a better understanding of what they mean for an individual with AS. The most common communication characteristics at each ORCA score level were derived using a statistical analysis of existing ORCA data. Vignettes describing typical communication behaviors at representative scores across the ORCA scale were developed to help understand what a specific score means in terms of communication behaviors. A survey of nearly 150 caregivers indicated that a score change of approximately 2 points represents a meaningful change in the ORCA score to everyday life.

Speaker: Emma Bauschard, Boston Children’s Hospital

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Looking Ahead: Increasing the number of caregivers surveyed and refining the CVI screening tool to more accurately capture CVI in individuals with AS is needed.

Summary: CVI is dysfunction in the visual processing pathways in the brain, resulting in vision problems that are caused by more than just ocular abnormalities. CVI is a leading cause of childhood blindness and can lead to difficulties in visual attention and recognition. CVI is correlated with developmental delays, epilepsy, or other genetic abnormalities, suggesting that individuals with AS may have an increased risk of CVI. CVI can improve dramatically with vision therapy, and understanding its presence in AS is vital to ensuring that those who experience CVI can get the proper therapeutic interventions.

To explore if people with AS are more likely to have CVI, the primary caregiver of 20 AS individuals were given a survey evaluating the individuals history of vision problems and evaluations, as well as a questionnaire about the observed vision function. Based on the answers, individuals were identified as positive or negative, with a positive identification suggesting the possibility of CVI. Approximately 40% of the individuals (8/20) were identified as positive for CVI, of which 3/8 had an existing CVI diagnosis. 60% of individuals (12/20) were identified as negative for CVI, of which 2 had an existing CVI diagnosis.

Speaker: Colin Juett, UCLA

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Looking Ahead: Studies are ongoing which will help to support a data package suitable for requesting to start a human clinical trial.

Summary: Human hematopoietic pluripotent stem cells (HSC) can be collected, cultured, and modified outside a patient’s body. This modification could be inserting a healthy copy of a missing gene, like UBE3A. When the cells are re-infused into the patient, the modified cells will re-populate the bone marrow, where they came from, start to grow and migrate throughout the entire body, including the brain. Edited HSCs have been used to treat numerous hematological and metabolic diseases, and the ability of the cells to reach the brain means there is potential to use modified HSCs to treat neurological diseases, like AS.

AS mice treated with HSC-GT where a healthy copy of UBE3A was added to the cells to restore expression showed improvements in motor and cognitive function relative to untreated AS mice. Delta power in treated AS mice was reduced to levels consistent with wild type (non-AS) mice.

Speaker: Niki Armstrong, MS, CGC, FAST

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Looking Ahead: Exploring ways to better characterize and understand UBE3A mutations and their resultant UBE3A function and continuing to add mutation AS individuals to GASR.

Summary: Mutations in the UBE3A gene are a known cause of AS, however, most mutations that cause AS are novel and are classified based on their predicted effect on UBE3A protein expression and function. The Global Angelman Syndrome Registry (GASR) catalogues UBE3A mutations, their locations, and their predicted effects on the protein.

Understanding the scope of the mutations, and their effects on UBE3A protein can aid in designing therapies that will be specifically effective for the mutation genotype of AS. Adding additional mutation AS individuals to GASR will strengthen the entire dataset.

Speaker: Adriana Gomes, MD, Rady Children’s Hospital/UCSD

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Looking Ahead: Continued analysis of the natural history data to further understand how AS symptoms impact each other, and how that might help with identification of potential biomarkers.

Summary: The Angelman Syndrome Natural History Study has enrolled more than 500 AS individuals over the course of 18 years, building a substantial dataset describing nearly all aspects of AS, which can be analyzed to gain understanding of symptoms, and how different symptoms may influence each other.

A significant percentage of AS individuals have GI symptoms early in life, and those symptoms persist throughout the life of the AS individual. Analysis of natural history data found an apparent correlation between GI symptoms and seizures. Participants without GI symptoms had a seizure prevalence of approximately 25%, while participants who reported multiple GI symptoms had a seizure prevalence of 53-100%.

Speaker: Bridgette Kelleher, PhD, Purdue University

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Looking Ahead: Continued collection and analysis of data from Project WellCAST to better understand and support the needs of caregivers.

Summary: Project WellCAST is an NIH supported effort to match caretakers of persons with rare diseases with personalized support that will meet their needs. Clinicians and staff involved in the project evaluated the effectiveness of peer coaching to support caregivers of persons with rare diseases, including 64 AS caregivers.

The team identified that peer-to-peer coaching was effective for improving outcomes regarding the mental wellness of caregivers, including caregivers of individuals with AS.

Speaker: Madelaine Gramling, Boston Children’s Hospital

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Looking Ahead: Continued analysis of the AS natural history data to identify additional areas of concern and potential targets for specific support or intervention.

Summary: Understanding the challenges and concerns of caregivers for individuals with AS is critical for providing appropriate support. Collecting data on these challenges directly from caregivers allows for the identification of unmet needs and gaps in care.

The team analyzed data from 193 participants from the Angelman Natural History Study, including individuals from each of the molecular subtypes. The analysis revealed that expressive communication is the most frequently reported concern by caregivers of AS individuals. Other frequently cited areas of concern include an AS individual’s ability to externalize problems and get appropriate sleep.

Speaker: Anne C. Wheeler, PhD, RTI International

Watch full presentation here.

Looking Ahead: Addition of cognitive testing to accompany the behavior lists, modifications to the behavior classifications to improve the clarity of the survey.

Summary: Anxiety in individuals with AS can present with different forms, and caregivers report that symptoms of anxiety can have a significant impact on the quality of life of both the individual with AS and the rest of the family, and it is important for these symptoms to be captured accurately. Because of the mixed presentation of anxiety in persons with AS, traditional anxiety measurements may not be fit for purpose, and new tools specifically designed to evaluate anxiety in AS individuals were developed.

Interviews with caregivers were conducted to identify common indicators of anxiety in their child with AS. These interviews resulted in a set of consistently observed behaviors, which were assembled into a list of 69 behaviors that can be ranked by frequency and severity to assemble a more complete picture of anxiety in an individual with AS.

Speaker: Linna Han, PhD, North Carolina State University (speaking on behalf of Albert Keung)

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Looking Ahead: Working with a contract research organization to validate and qualify the assay to be used on clinical samples.

Summary: A sensitive assay that can determine if UBE3A protein is functional is a valuable tool for AS research and drug development. The Keung lab has developed a fluorescence-based assay that can detect UBE3A activity in cell lysates when UBE3A is at a very low concentration.

The sensitivity of the functional assay was refined to be able to detect the presence of as little as 1 nanomolar UBE3A in cell lysates. The assay was also adapted to be able to run in a high throughput setting, making it more useful for drug discovery.

Speaker: Morty Razavi, PhD, SISCAPA Assay Technologies

Watch full presentation here.

Looking Ahead: Additional characterization of UBE3A protein in CSF of AS individuals with different molecular subtypes, and age-matched controls, will help to support of the UBE3A detected in neurotypical samples is truly neuronal in origin.

Summary: All therapies for AS which replace UBE3A protein will ultimately strive to find a way to measure protein levels before and after treatment and compare these protein levels with other biomarkers and outcome measures in an effort to correlate this with clinical benefit. Being able to track the amount of UBE3A protein being produced and comparing that with changes in a patient’s clinical outcome measures, such as the Bayley-4, is critical for building confidence that the therapy is working as expected. Outside of taking brain samples, measuring UBE3A in the cerebrospinal fluid (CSF) is the closest way to get a picture of what is going on in a patient’s brain before, during, and after treatment. An assay that can accurately and sensitively measure UBE3A in CSF is important for future clinical development. FAST has funded this work to develop an assay that can be broadly shared across the globe with any researcher or sponsor working on UBE3A replacement.

Following an optimization process, SISCAPA developed a highly specific assay that can detect UBE3A protein in CSF at concentrations as low as femtogram per milliliter, 150x more sensitive than other assays reported. The assay is now available to researchers, clinicians, and industry partners to use.

Speaker: Joel Matthews, PhD, Ionis Pharmaceuticals

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Looking Ahead: Follow up studies to understand how the levels of Ube3a in the brain and CSF are related and if contamination of the CSF collection in rodents could have contributed to a failure to detect differences between those treated and untreated.

Summary: People with AS who are not on ASO therapies have variable amounts of UBE3A in their CSF. To better understand the source of this variability, a study was conducted in rats to examine the relationship between Ube3a protein levels in the brain and in the CSF. Rats were treated with an ASO that reduced Ube3a mRNA, resulting in reduced Ube3a protein in all cells of the brain. 8-weeks after the ASO treatment, the amount of Ube3a protein in the brains and CSF of the rats were measured.

Following treatment with the ASO designed to reduce Ube3a, animals in the treated groups had lower levels of Ube3a in the cortex and spinal cord compared to untreated animals, as expected. However, the Ube3a levels in the CSF were the same across all groups, suggesting that the amount of Ube3a in the CSF may not reflect the amount of Ube3a in the brain.

Speaker: Donald B. Kohn, MD, University of California, Los Angeles

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Learn more about the program here.

Looking Ahead: Preparation of this type of gene therapy for a clinical trial includes collecting additional safety and efficacy data, manufacturing activities, and meeting with regulatory agencies to support moving this program forward.

Summary: Hematopoietic stem cells (HSC) come from bone marrow, umbilical cord blood, or mobilized blood cells, and ultimately produce all the cells found in blood. HSCs can be used to treat genetic diseases by replacing the patients' genetically abnormal HSCs with corrected, or normal, HSCs. The cells will populate the bone marrow with new healthy cells. This approach of transplanting HSCs has been used to cure multiple diseases, however, one of the drawbacks of “traditional” HSC transplant therapy is that it requires a genetically matched donor (allogeneic), which is not always available. One solution to this problem is to harvest the patient’s own HSCs (autologous), modify them outside the body, and then inject the modified cells back into the patient, a process known as autologous HSC gene therapy. Autologous HSC-GT not only eliminates the need for a donor but also eliminates the risk of complications from introducing donor cells to the patient, where an immune reaction can occur (graft versus host reaction).

To use HSC therapy to treat AS, the patient’s own stem cells are removed from their blood, modified in a lab to add the UBE3A gene into the cells, and then injected back into the body where they seed into the patient’s own bone marrow. These modified cells then are released and can cross the blood brain barrier and become resident brain inflammatory cells, or microglia, this naturally occurs throughout life. Once the modified microglia have taken up residence in the brain, they will start producing the UBE3A protein, secrete it into the brain tissue and it will be taken up by surrounding neurons, with the hopes of enabling them to start functioning more normally. The ability of autologous HSC-GT to correct AS was demonstrated in AS mice. The treated with the modified HSCs showed significant improvement in multiple motor and cognitive behavioral tests relative to the AS untreated animals. While those early experiments were encouraging, it was later discovered that the constructs used to modify the HSCs in those experiments carried a mouse promoter that had a risk of causing cancer in humans and would not be suitable for treating people.

To translate the success observed in the initial AS mouse experiments to a therapy that could be used to treat people, the team designed novel constructs that would produce functional Ube3a but not carry that additional risk. Finding a new promoter with the human UBE3A construct that is function is the key to moving this program forward to human clinical trials, and those experiments are underway and look very promising.

Speakers: James M. Wilson, MD, PhD, GEMMABio, Elizabeth Berry-Kravis, MD, PhD, Rush University Medical Center

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Looking Ahead: As of this presentation 2 trial sites were disclosed on clinicaltrials.gov and additional sites in the US and in Canada will be opening in the coming months. The first patient in this trial had received the therapy, and the trial will include both adults and pediatric participants with AS that have a deletion, UPD or ICD genotype.

Summary: Gene replacement therapy is a promising way to treat diseases where the problem stems from a missing or defective gene. Adeno-associated viruses (AAV) are one of the most common ways to deliver gene therapy to a patient; AAV’s are not known to cause disease in people; they can carry a healthy copy of the missing or non-functional gene and deliver it different organs, like neurons in the case of AS. These properties make AAV gene replacement therapy an appealing option for treating AS. MVX-220 is an investigational gene replacement therapy utilizing the AAV-hu68 vector, which expresses the human UBE3A gene for the potential treatment of Angelman syndrome.

The first in human Phase 1/2 trial to evaluate the safety and tolerability of MVX-220 began in 2025. The design of the MVX-220 Phase 1/2 trial will assess safety and tolerability and evaluate efficacy utilizing outcome measures selected from work done by ABOM and incorporating learnings from the PFDD meeting.

Speaker: Andrew Steinsapir, MBA, Apertura Gene Therapy and Deerfield Management

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Looking Ahead: Building an appropriate data package demonstrating safety and efficacy, which can be used to support clinical trials in 2026 will drive the potential use for other disorders like AS.

Summary: AAV capsids exist with different properties and modifications, and which organs they target depends on these differences. The route of delivery to achieve the best spread, or biodistribution, to the target organ is important. Most of the capsids currently in use in clinical trials have limited ability to cross the blood brain barrier (BBB), meaning AAV gene therapies which target the brain must be delivered directly into the cerebral spinal fluid or the brain tissues. An AAV capsid that could be delivered in the peripheral vein, or intravenously (IV), that could actually cross the BBB, and be delivered to the neurons of the entire brain, is an ultimately goal for brain targeted gene therapy. Many factors are important to understand as these capsids are being developed, with the most important being to understand the safety in humans.

The Apertura team designed novel AAV capsids which specifically bind to a receptor found at the blood brain barrier, called the transferrin receptor, or TfR1, helping to get the AAV to cross into the brain by the blood vessels. Studies on ongoing to understand the safety of these capsids for the potential future use in disorders like AS.

Speaker: Raphael Bendriem, PhD, Arbor Biotechnologies

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Summary: CRISPR gene editing has been shown to be an effective way of unsilencing paternal UBE3A and restoring UBE3A gene expression. Arbor’s approach uses novel CRISPR gene editors to target the UBE3A-ATS and restore paternal expression. An initial high throughput screen produced approximately 300 candidate editors, which were further screened in human neuronal cultures to generate a set of candidate molecules which will be tested in animal studies to ultimately identify a future clinical candidate.

To enable screening and selection of the best molecules, a novel phenotypic assay measuring hyperexcitability of AS neurons was developed, which allowed for additional validation of the candidate molecules. The top gene editor and guide RNA candidates show complete reversibility of hyperexcitability in the neurons.

Speakers: Yong-Hui Jiang, MD, PhD, Yale School of Medicine, Jiangbing Zhou, MD, PhD, Yale School of Medicine, Allyson Berent, DVM, DACVIM, FAST and AS²Bio.

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Looking Ahead: The steps required to take a potential therapy from the lab bench to testing in human trials is complex. These steps are underway with this program. The resulting data will inform the safety and possible efficacy of this investigational gene editing platform to initiate a Phase 1/2 clinical trial for Angelman syndrome in the future.

Summary: CRISPR gene editing has been used to treat genetic diseases, however, delivering a genome editor to the brain has been challenging, as most of the common ways to package a genome editor, such as an AAV or lipid nanoparticle are too large to cross the blood-brain barrier, or difficult to get into neurons, necessitating a search for alternative approaches. The stimuli responsive traceless engineering platform (STEP) is a novel compound that can carry a ribonucleoprotein (RNP) containing a CRISPR gene editor across cell membranes and deliver it into neurons. These STEP-RNP complexes are highly efficient editors in human neurons and cortical organoids, as well as rodents, making exploration into larger animal models important.

STEP-RNP complexes targeting the Ube3a-ATS were administered to AS mice of different ages (newborn to adult). The animals treated with STEP-RNP showed improvement in motor coordination, cognition, and EEG delta power relative to untreated animals, regardless of their age when treated. STEP-RNP treatment also suppressed seizure susceptibility in newborn and adolescent AS mice relative to untreated animals.

Speaker: Allyson Berent, DVM, DACVIM, FAST and AS²Bio.

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Summary: Clinical trials are crucial for testing the safety and efficacy of new therapies for AS and must be conducted for every new drug or biologic. Participants in clinical trials and their families are partners in the effort and are taking on an often-unknown risk. Parents of children with AS who are participating in a clinical trial need to be able to ask questions, understand exactly what will happen to their child, and understand their responsibilities and expectations as participants in a trial.

Parents can find a trial that may be suitable for their child by searching reputable sources like clinicaltrials.gov, cureangelman.org, or angelman.org, and then discussing the options with their child’s care team. Once a trial has been identified, the enrollment process involves multiple steps, including screening, discussion and signing of informed consent, baseline assessments, receiving the actual investigational drug, and follow-up visits and assessments. It is critical for parents to fully understand the goal of the trial and the expectations and requirements for participants. Parents should also fully understand the informed consent form and ask any questions they have before signing.

Once a child is participating in a trial, parents should respect the confidentiality and integrity of the trial by not sharing information about the trial on social media or in public forums or discussing any perceived benefits of the drug they may be observing in their child. Any side effects should be immediately reported to the study doctors but should not be shared on social media or in discussion forums. For consistency, the same caregiver should be responsible for filling out questionnaires and data points throughout the trial period.

Parents of a child who is participating in a clinical trial should document their child’s journey, as well as any impacts their participation may have on the family. Parents should feel empowered to ask any questions they have to the study doctors at study visits, however they should be careful not to disclose their child’s participation if they are asking direct questions about their child in a public setting.

Speaker: Brenda Vincenzi, MD, Oak Hill Bio

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Learn more about the program here.

Looking Ahead: Initiation of enrollment of the BEACON study.

Summary: Oak Hill Bio has taken over the development of rugonersen, an ASO designed to unsilence paternal UBE3A by knocking down the UBE3A-ATS, from its original developer, Roche. In an open-label Phase 1 study (TANGELO), treatment with rugonerson led to reduction in abnormal brain activity as measured by EEG, as well as improvements in cognition and expressive communication.

Full results from the Phase 1 study were published, and plans for a double-blind, placebo-controlled Phase 3 pivotal study known as the BEACON study are finalized and expect to begin in early 2026.

Speaker: Kimberly Goodspeed, MD, Ultragenyx

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Looking Ahead: Enrollment in Aspire, a double-blind, placebo-controlled Phase 3 study has completed, and data collection is ongoing. A phase 2 study (Aurora) which includes additional ages and genotypes was opened for enrollment in October 2025 and enrollment will continue in 2026.

Summary: GTX-102 is an ASO designed to unsilence paternal UBE3A by knocking down the UBE3A-ATS. A recently completed open-label Phase 1/2 clinical study observed that treated individuals showed improvements in receptive communication, cognition, balance and coordination, and sleep, amongst other things. GTX-102 has an acceptable safety profile that supported continued development.

The challenges of using a single primary efficacy endpoint in a disease with a heterogenous presentation led to the development of the multidomain responder index (MDRI). The MDRI is an analysis tool that captures changes in multiple domains that have been identified as being important to patients and caregivers and are independent from each other. Using the MDRI for AS provides a more accurate representation of the impact of GTX-102 on patients which is global and not in a single domain.

Speaker: Candice Junge, PhD, Ionis Pharmaceuticals

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Looking Ahead: Continued enrollment in the HALOS and REVEAL studies will continue through 2026. Publication of the results from the Phase 1/2 multiple ascending dose study is expected in the future. Initiation of a phase 3 study in AS individuals with UPD or ID (CHAMPION) is planned for 2026.

Summary: ION582 is an ASO designed to unsilence paternal UBE3A by knocking down the UBE3A-ATS. An open label, multiple ascending dose Phase 1/2 study (HALOS) has completed and has transitioned into an ongoing open label extension. In the open label extension, patients under two years old are also eligible for treatment. Patients receiving ION582 have demonstrated improvements in expressive communication, and suppression of EEG delta power.

The first participant under two was dosed as part of the HALOS open label extension. A double-blind, placebo-controlled phase 3 study (REVEAL) has been initiated, and the first participant was dosed in June 2025.

Speaker: Shady Sedhom, PhD, F. Hoffmann-La Roche Ltd.

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Looking Ahead: Data from this study is expected to be available in Q2/3 of 2026 and will be shared with the AS community when available.

Summary: Deletion AS includes the loss of genes in addition to UBE3A, including 3 GABA-A receptor subunits, and loss of the GABA gene cluster, which is thought to contribute to the increased severity of symptoms in those with deletion AS relative to the other subtypes. Alogabat is a small molecule that enhances the function of the GABA-A-a5 receptor, which has reduced function in individuals with deletion AS. Restoration of the activity of GABA-A-a5 receptor may normalize the EEG b-band phenotype in deletion AS individuals and improve overall AS symptoms. Alogabat has been evaluated in healthy volunteers and in a phase 2 trial in autism and has an acceptable safety and tolerability profile to support further development.

An open-label Phase 2a study of Alogabat in children and adolescents with deletion AS is fully enrolled with 48 participants ages 5-17. No results were shared.