Highlights of the 2026 STXBP1 Research Roundtable Meeting

The 2026 STXBP1 Researcher Roundtable took place on July 16 and 17 in Philadelphia. More than 100 researchers, doctors, and industry partners from around the world attended. The meeting focused on three main goals: understanding how STXBP1 and different STXBP1 gene changes affect the body, sharing progress on possible treatments, and preparing the tools needed for future clinical trials.

STXBP1 and Gene Changes

The first talks focused on how STXBP1 may help the brain and nerve cells develop. Bianca Graziano from UCSF showed that the STXBP1 protein is found near tiny hair-like structures called cilia. In the nose and airways, cilia help move mucus and trapped particles out of the lungs. Her work suggested that harmful STXBP1 changes may weaken this movement. She also found STXBP1 near similar structures on brain cells, where they help guide early brain development through a signal called sonic hedgehog, or shh. When STXBP1 was missing, this process did not work normally. Faye McLeod from Newcastle University studied fetal brain tissue to see what happens when STXBP1 levels are lowered. She focused on a region of the brain called the subplate, where early neuron connections and organization of the cortex begin. Lower STXBP1 made nerve cell activity weaker and less coordinated. It also affected proteins involved in guiding nerve fibers and forming synapses. Tao Yang from the University of Michigan used mouse models and found that Stxbp1 is important for nerve cell survival during brain development. It also helps move key structural proteins to the cell membrane so dendrites can form properly. Tao shared early evidence that removing Stxbp1 in mice can cause developing neurons to migrate too far, disrupting normal cortex organization.

Other speakers focused on specific STXBP1 gene changes, called variants. Elisa Waxman from CHOP described a method to test whether a variant makes the STXBP1 protein break down too quickly, bind too weakly to its partner protein syntaxin, or both. Ana Carreras Macaro from Neurospector studied 400 STXBP1 missense variants, including many variants whose effects were unclear. Her team was able to classify 99 of these uncertain variants as likely disease-causing or likely harmless. Adam Rossano from CHOP/UPenn examined how a STXBP1 variant affects a neuron’s ability to release neurotransmitters. He discovered that the variant causes a delay in the ‘docking’ of presynaptic vesicles to the neuronal membrane and this results in less synchronous neuronal activity.

Developing Possible Treatments

Several talks described new tools for testing possible treatments. Illana Gozes from Tel Aviv University and Thomas Vogels from InnoSer Laboratories described two new Stxbp1 mouse models. Each model carries a specific STXBP1 variant seen in patients. These models may help researchers test treatments that are designed for particular types of STXBP1 changes. Omer Revah from Hebrew University of Jerusalem discussed human cortical organoids, which are small brain-like structures grown in the lab. These organoids can be made with STXBP1 variants and used to test drugs or other therapies before they are tried in people.

Other researchers discussed ways to increase the amount of working STXBP1 protein. Ben Prosser from the University of Pennsylvania explained that raising STXBP1 protein levels in patient cells has been difficult. Some treatments increase STXBP1 message, called mRNA, but the protein does not rise as much. This may be because cells have limited amounts of STXBP1’s partner protein, syntaxin-1, or because different ‘pools’ of mRNA are made into protein at different rates. Gad Vatine from Ben-Gurion University described an RNA editing approach called ADAR that may be able to repair the R406H STXBP1 variant and could possibly be adapted for about 55 STXBP1 variants. Paula Vij from UC Davis shared progress on a CRISPRa approach that increased STXBP1 protein in several patient-derived cell lines. Luis Williams from Quiver Biosciences described work on antisense oligonucleotides, or ASOs, designed to raise STXBP1 protein; his team has several promising candidates. Zach Grinspan shared an update on a 4-phenylbutyrate, or Ravicti, study. Across several genetic developmental epilepsies, including 10 children with STXBP1-related disorder, the drug reduced seizures in about half of patients and may have had mild developmental benefits for a smaller group.

Gene replacement therapy was another major topic. Holly O’Shea from the University at Buffalo and Brandon Brown from CHOP each described early work on AAV gene therapies for STXBP1-related disorder. AAVs are delivery tools that can carry a working gene into cells. Holly O’Shea’s work focused on designing a gene delivery system that could increase STXBP1 gene expression in the mouse brain. Brandon Brown described a newer AAV capsid, or outer shell, that increased STXBP1 mRNA and protein in the mouse brain at lower doses than older AAV9-based approaches. Andrew Steinsapir from Apertura discussed a capsid called CapX, which is designed to reach the brain through a receptor on the blood-brain barrier and could allow gene therapy to be given through an IV. Yong Cheng from Minzu University in China described an AAV9-based STXBP1 gene therapy that worked in mice and non-human primates. That treatment is delivered directly into the brain’s fluid-filled space and is now in a clinical trial in China, where the first patient was dosed in March.

Getting Ready for Clinical Trials

Several talks focused on biomarkers. Biomarkers are measurements that can help doctors understand how a disease is changing or whether a treatment is working. Mike Boland and Fan Yi from CHOP discussed ways to measure STXBP1 protein in blood or cerebrospinal fluid, the fluid around the brain and spinal cord. This could be important for future treatments that are meant to increase STXBP1 protein in the brain. Wendy Gold from the University of Sydney used a broad “omics” approach, which looks at many biological molecules at once, and found signs that the immune system may be more active in people with STXBP1-related disorder. Julie Orlando and Jillian McKee from CHOP shared data suggesting that body movement patterns and EEG brain wave patterns may also become useful biomarkers.

Natural history studies were also a major focus. These studies follow people over time to learn how a condition changes with age. Ganna Balagura from the University of Genoa and Hannah Stamberger from the University of Antwerp shared data from the ESCO registry and natural history study. Several researchers from CHOP, including Ingo Helbig, Sam Pierce, Kristin Cunningham, Sarah Tefft, Maya Mosner, and Carlyn Glatts, and Andrea Miele and Megan Abbot from Children’s Colorado, presented findings from the STARR Study. With 180 participants enrolled and the study entering its third year, STARR is collecting information on seizures, movement, behavior, self-care, thinking skills, language, and autism-related traits. The data suggest that people with STXBP1-related disorder may fall into three broad groups: some change over time, some remain fairly stable, and some do not follow the most common pattern for their age. These studies should help researchers choose the right outcome measures for future clinical trials.

Overall Takeaway

Overall, the meeting showed that STXBP1 research is moving quickly. Researchers are learning more about how STXBP1 affects brain development, how different variants change protein function, and which treatment approaches may be worth testing further. At the same time, clinical teams are building the biomarkers and natural history data needed to design strong clinical trials. More work is still needed, but the field is becoming better prepared to test treatments that could help our STXers.