Strides in STXBP1 Research: Oct & Nov
What’s new in October & November of 2025?
Scientists at the pharmaceutical company Biogen published a paper that demonstrated an AAV-based STXBP1 gene therapy vector rescued presynaptic function in cultured human iPSC-derived neurons in which the STXBP1 gene was knocked out (STXBP1-KO). First, they showed how they could measure the amount of electrical activity in a plate of normal neurons. This included spontaneous activity from individual neurons and synchronized activity known as ‘network activity’. Next, using a set of specific drugs, they proved that this electrical activity was due to synaptic activity, i.e. the release of glutamate from presynaptic terminals and activation of a specific type of receptor on postsynaptic terminals. When they tested the STXBP1-KO neurons, they found a loss of both spontaneous and network activity, which they were able to show was due to a significant decrease in the amount of glutamate released from presynaptic neurons. Finally, they treated the STXBP1-KO neurons with an AAV-STXBP1 vector and were able to recover both spontaneous and network activity, and this recovery was dependent on the dose of the AAV-STXBP1 vector used.
Researchers from CHOP/UPenn conducted a study to test if wearable sensors could be used to evaluate tremors and movement abnormalities in STXers. They attached sensors, which are about the size of a smartwatch, to the upper arms and forearms of 31 individuals with STXBP1-RD and asked them to reach for a target – they compared the results to results from 19 typically developing controls. The study found that most people with STXBP1-RD showed clear differences in how they moved compared to typically developing peers. Their reaching movements were slower, less smooth, and had weaker acceleration. Importantly, smoother and faster movements were linked to stronger motor, communication, and cognitive skills, while more irregular tremor patterns were tied to poorer developmental outcomes. In addition, the sensor-based measurements were able to predict the presence of tremor with high accuracy and found about two-thirds of the STXer tested had tremors that were irregular and unstable. This was a larger number than expected, suggesting that tremor may be an underappreciated symptom. Overall, the results show that wearable sensors can reliably capture motor control differences and tremor in this population, offering a powerful tool to track symptoms and support future treatment trials.
A team led by researchers at Duke University published their findings on using the Observer-Reported Communication Ability (ORCA) measure in children with neurodevelopmental disorders. This study measured communication abilities in children with 12 rare NDDs, including STXBP1-RD, by interviewing 115 caregivers and 9 clinicians. It aimed to improve the measurement of communication skills for use in clinical trials. Researchers focused on expressive, receptive, and social communication, finding common behaviors like requesting objects, responding to directions, and seeking attention, but also identified new communication concepts such as expressing feelings, likes/dislikes, and humor. The study highlighted the wide range of communication methods used by children, including verbal speech, gestures, eye gaze, and assistive devices, and emphasized the importance of caregiver insights in understanding these behaviors. The findings will help refine the ORCA measure, which was originally developed for use in children with Angelman syndrome, to better assess communication skills across different NDDs and support meaningful improvements in clinical care and trials.
A group of Chinese scientist examined the effect of Stxbp1 haploinsufficiency on the serotoninergic system, a neurotransmitter system in the brain that is important in regulating mood, movement, and behavior. Using worm and mouse models of STXBP1-RD, they found that serotonin-producing neurons were fewer in number, their connections became weaker, and serotonin levels dropped. Their mice demonstrated the same characteristic phenotypes as described in other Stxbp1+/- mice; seizures, tremors, motor abnormalities, behavioral (anxiety and aggression), and cognitive problems (learning and memory). To determine what role the reduced serotoninergic system played in these phenotypes, the researchers developed a mouse model where Stxbp1 was only reduced in the serotonin neurons but was normal in other types of neurons (e.g. glutamatergic and GABAergic). They found these animals still developed anxiety and aggression but did not demonstrate cognitive impairments and had reduced seizure activity. Treating these mice with a clinically available psychiatric drug reduced anxiety and aggressive behaviors.
Chinese researchers published a paper looking at a type of breast cancer (triple negative breast cancer, TNBC), which doesn’t respond well to common cancer treatments, and genes that are linked to the body’s interferon system, a group of proteins important in fighting infections and regulating the immune system. They found that STXBP1 was abnormally expressed in TNBC cells. The researchers showed that high STXBP1 protein levels were tied to worse patient outcomes and greater immune suppression, suggesting the protein may play a role in helping the tumors evade the immune system. They also found evidence that STXBP1 is at the center of several “molecular conversations” (networks of different types of RNAs talking to each other) that appear to push TNBC forward. Because of this, STXBP1 could serve as a biomarker for tumor growth and expected patient outcomes as well as a druggable target – reducing STXBP1 activity might help stop TNBC cells from growing.
Scientists from the University of Houston looked at how a protein called Syntaxin 3B (STX3B) interacts with STXBP1 and another protein called arrestin 4 to help our eye’s light-sensing cells (rods and cones) work properly. They found that STXBP1 plays a crucial supporting role in how cones (the cells in our eyes that allow us to see color) stay healthy. When STX3B is removed from cones, STXBP1 levels drop significantly. This does not occur if STX3B is removed from rods, showing that cones depend more heavily on STXBP1. They also found that STXBP1 forms part of a light-dependent complex: in darkness, arrestin 4 binds more with STX3B, but in light, arrestin 4 binds with STXBP1, this helps cones adapt to changes between light and dark. Without STXBP1, cones become dysfunctional and degenerate.
A Chinese group developed a computer-based tool to help doctors diagnose temporal lobe epilepsy (TLE). By analyzing genetic data from hundreds of patients, the group built a ‘deep learning’ model that can spot TLE with near perfect accuracy using just 10 key genes. One of the most important of these genes is STXBP1. The model showed that STXBP1 levels can either increase or decrease the likelihood of having TLE, depending on how it interacts with the other genes.
A Turkish group published the results of targeted epilepsy gene panel (TGP) screening on 129 children diagnosed with developmental and epileptic encephalopathy (DEE). The TGP revealed 29 of the 129 children had a pathogenic or likely pathogenic variant in one of the 55 genes in the TGP, including 3 children with variants in STXBP1; the third most common variant found.
