Movement disorders significantly impact the daily lives of individuals with Angelman syndrome, including dystonia, tremors, stereotypies, and other poorly understood or unclassified movements. These disorders interfere with regular activities and require better characterization and classification to develop effective treatments.

To address this critical need, four of our leading clinicians—Elizabeth Berry-Kravis, MD, PhD (Rush Univ Medical Center, Chicago), Wen-Hann Tan, MD (Boston Children’s Hospital, Boston), Robert Carson, MD, PhD (Vanderbilt University Medical Center, Nashville) and Jean-Baptiste Le Pichon, MD, PhD, FAAP (Children’s Mercy Kansas City)—will be leading this groundbreaking work.

This project builds on the groundbreaking work previously supported by ASF, continuing to advance our understanding of movement disorders in Angelman syndrome. Through a multi-site study involving 120 individuals across four leading medical centers, researchers aim to establish a comprehensive understanding of these movement challenges. By creating a video library reviewed by movement disorder experts and testing wearable devices to monitor movements in real time, the study will provide essential tools for diagnosing and tracking these disorders.

The findings from this research will enhance clinical care, inform therapeutic development, and offer new ways to measure the effectiveness of emerging treatments—ultimately improving the quality of life for individuals with Angelman syndrome.

This project is jointly funded by the Angelman Syndrome Foundation and the Pritzker Family.

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.

Many treatments for Angelman syndrome that are in development aim to turn on the silent paternal UBE3A gene to increase UBE3A in the brain. We don’t yet know if this is safe for individuals who already have too much UBE3A activity.

Some people with Angelman syndrome have missense mutations. These are small changes in the UBE3A gene where just one part of the protein is different. These tiny changes can have big effects.

• They may not cause any problems
• They may reduce UBE3A function, or
• They may make UBE3A too active (gain-of-function)

Right now, it’s hard for doctors to tell which type a child has, and that makes treatment decisions more complicated.

This study will test antisense oligonucleotide (ASO) treatment in mice with a gain-of-function mutation to see how it affects their behavior, health, and safety.

This research will move us toward treatments that are effective, safe, and tailored to every person with Angelman syndrome.

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