By funding this groundbreaking work from Ben Philpot and his team, the Angelman Syndrome Foundation is investing in one of the most direct paths toward a true treatment for Angelman syndrome. This research tackles the core biology of Angelman syndrome by focusing on how to turn on the intact but silenced paternal UBE3A gene, which represents one of our most promising therapeutic strategies.

Because individuals with Angelman syndrome lack the maternal copy of UBE3A, reactivating the paternal gene could restore the function that is missing in the brain. Until now, scientists have not been able to study paternal UBE3A silencing at the depth and scale needed to pinpoint what controls it. Dr. Philpot’s team has changed that by building a powerful reporter mouse model and the capability to grow hundreds of millions of neurons, making it possible to run the first genome-wide CRISPR screen to identify the genes responsible for keeping paternal UBE3A turned off.

By uncovering these targets and testing whether they can be safely modulated with drugs, this work provides a clear roadmap for designing therapies that directly unsilence the paternal gene. For the Angelman community, this means deeper biological understanding, precise therapeutic targets, and meaningful progress toward treatments that address the condition at its source.

By funding this important work led by Dr. Danny Miller, the Angelman Syndrome Foundation is helping bring cutting-edge science directly to our community. Advances in long-read sequencing offer an important breakthrough by uncovering the precise genetic changes behind Angelman syndrome, even when previous tests could not.

While most individuals have known causes, a meaningful number either carry difficult-to-interpret variants or have no identified genetic change at all. Without clear answers, families often face years of uncertainty, repeated testing, and limited access to research or treatment opportunities.

Long-read sequencing can change this by pinpointing hidden or complex variants, determining whether a UBE3A change is maternal, and identifying cases that earlier technologies missed. Unlocking this information not only offers families clarity, but it provides access to clinical trials, guides scientists toward more precise therapeutic targets, and strengthens our understanding of Angelman syndrome at its core.

By investing in this work, ASF is helping deliver knowledge our community has never had before—and that knowledge is a critical step toward more personalized therapies and ultimately, a treatment.

Around 10% of Angelman syndrome cases are caused by specific changes in the UBE3A gene, but many of these genetic variants are classified as “uncertain” or “conflicting,” making it difficult for doctors to determine their impact. Adding to the complexity, some mutations increase UBE3A activity, leading to different symptoms than the typical loss of function seen in Angelman syndrome.

Our lab has developed a new biosensor to accurately measure UBE3A activity, even at normal levels found in the body. This tool can distinguish harmful mutations that reduce or increase UBE3A activity from those that have no effect. Early tests have shown its ability to classify known mutations with high accuracy.

Why It Matters

This biosensor could revolutionize diagnosis and research by:

1. Helping classify uncertain UBE3A variants.
2. Measuring UBE3A activity in patient-derived cells.
3. Providing clearer answers for families and supporting better treatments for Angelman syndrome.

By bridging the gap between genetic testing and clinical care, this tool offers new hope for understanding and managing UBE3A-related conditions.

One of my long-term goals is to develop a disease-modifying treatment for Angelman syndrome. Treatments like ASOs and genome editors that unsilence the paternal UBE3A allele show incredible promise. With support from the ASF, our lab was the first to show that Cas9-based genome editors can be used to unsilence the dormant paternal UBE3A allele in mouse and human neurons. One of the major remaining challenges has been determining if individuals with small mutations that alter UBE3A protein are likely to develop Angelman syndrome. The biosensor that we will develop as part of this project has the sensitivity to determine if UBE3A is abnormally low or high in cells, including brain and blood cells. This biosensor could be used to identify those individuals who might benefit from ASOs and genome editors that are in development for the treatment of Angelman syndrome.

– Mark Zylka, PhD

A classic phenotype of AS has been described which includes developmental delay, intellectual disability, speech impairment, gait ataxia and a happy demeanor. However, these features are not apparent in infancy. Further, initial symptoms of developmental delay are non-specific, which often complicate a diagnosis. The underlying molecular mechanism of AS is complex, and is known to be caused by methylation defects, deletions, and pathogenic single nucleotide variants in UBE3A, currently requiring multiple clinical tests to access. Taken together, despite the prevalence of AS, many patients do not receive a timely molecular diagnosis, may receive an incorrect diagnosis, or receive no diagnosis at all.

As precision therapeutics are increasingly developed, including ASOs which have shown tremendous promise in animal models, receiving a molecular diagnosis becomes exponentially more important. This project will address the current limitations of diagnostic testing for AS by utilizing a novel long read (LR) based sequencing approach, capturing multiple disease categories and variant types in a single economical test.

Individuals with Angelman syndrome (AS) are known to have an increased likelihood of exhibiting challenging behavior, especially in situations that are anxiety provoking. These behaviors substantially affect family functioning and caregiver mental health. However, there is not a well-established and validated measurement that helps capture the frequency, nature, and severity of challenging behavior in people with intellectual disability, much less in conditions like AS, where communication challenges are a significant problem.

The FDA developed a series of four methodological patient-focused drug development (PFDD) guidance documents which highlights the importance of using patient input to identify endpoints that are important and valid. As several potential future therapies for AS are being developed, an assessment that appropriately and objectively measures behavioral symptoms is needed.