Highlights from the Summit+ Researcher Roundtable

On Friday August 19, 2022 the STXBP1 Foundation held its Researcher Roundtable meeting in connection with the Summit+ Family Meeting. Over 70 researchers from as far away as Australia met to share and discuss the latest in STXBP1-related clinical and basic research.

The meeting kicked off with Board member Jared Barnum sharing his family’s journey with his daughter Georgia and her diagnosis with STXBP1 disorder. This began the coming together of researchers and families, which made this year’s Summit so successful and rewarding.

The morning half of the meeting focused on clinical updates and clinical trial readiness; Dr. Ingo Helbig and his team at Children’s Hospital of Philadelphia (CHOP) started us out. Dr. Helbig posed 3 questions relating to how we can better understand the variations in symptoms and mutations in STXBP1, gain a greater appreciation of the disease trajectory over time, and ultimately generate a predictable developmental disease model that can be used to better evaluate new drugs and therapies. Kim Thalwitzer, from his team, discussed a natural history study looking at German STXBP1 patients. This study found that patients with spastic seizures were less likely to have age-appropriate motor and communication skills compared to STXBP1 patients without seizures. Julie Xian described how she is constructing a clinical/symptomatic time course of STXBP1 by using electronic medical record data from both Ciitizen and CHOP. She has found an association between the type of mutation a patient has and the risk of different types of epilepsy. Similar to the findings in the German study, spasms in the first year of life are associated with the delay of some developmental milestones; however, most individuals still achieve milestones in the first 5 years of life. Katie Rose Sullivan, from the CHOP group, presented her work on creating a Disease Concept Model for STXBP1, which has helped uncover some underappreciated symptoms, like gastrointestinal and respiratory problems, in STXBP1 patients. Together, the CHOP presentations showed just how much better we understand STXBP1 disorder today than we did just a couple of years ago; so much progress has been made.

Dr. Zach Grinspan presented an update on his clinical trial of phenylbutyrate (Ravicti) to treat STXBP1 seizures. While the results are still early, it does appear that some patients with tonic, absence, or focal seizures are responding to the drug, that is, having fewer or no seizures. On the other hand, the drug does not appear to have had any effect on seizures for either of the two patients suffering epileptic spasms.

The development of a new European STXBP1 Consortium (ESCO) was discussed by Dr. Ganna Balagura from VU Amsterdam and the University of Genoa. The goal of ESCO is to promote clinical and pre-clinical research on STXBP1 and synchronize diagnosis and clinical assessments across several European countries, so that STXBP1 patients are medically viewed and evaluated in the same way regardless of what country they live in. The need for this ‘synchronization’ was illustrated in a figure she presented showing how various STXBP1 symptoms were differentially noted by physicians in the Netherlands versus Italy.

The morning session was finished off by two talks focused on electroencephalography (EEG) as a potential biomarker for STXBP1. Dr. Jay Pathmanathan, from Beacon Biosignals, discussed how machine learning and computers could be used to look for changes in EEG that are specific to STXBP1 patients. Dr. Elena Gardella, from the University of South Denmark, showed that EEGs from the back part of the brain were different in STXBP1 patients compared to patients with other types of neurodevelopmental epilepsies and that STXBP1 patients could be clustered into two different categories based on their EEG and these correlated with some clinical symptoms. This work is very important because it could lead to using EEGs as a way to see if novel drugs or therapies are working before a patient shows any outward signs that the drug is having an effect.

The afternoon session of talks was focused on animal and cellular models of STXBP1 and the development of potential therapeutic strategies to treat STXBP1. Dr. Scott Baraban, from the University of California San Francisco, who has developed zebrafish models of STXBP1 led off these talks. Because zebrafish can be bred easily in large numbers, they are an animal model that can be used for large scale drug testing. He has used them to identify potential drug candidates, including clemizole and trazodone, for the possible treatment of STXBP1. Dr. Wu (Charles) Chen from Baylor, who is a post-doctoral fellow in Dr. Mingshan Xue’s lab, described their STXBP1 mouse model and how it has been used to show that STXBP1 gene replacement using an AAV-viral vector can stop seizure activity and restore several behavioral abnormalities, including motor and cognitive problems, in these mice. In another talk, Dr. Francisco J. Esteban, from the University of Jaen in Spain, described how transplanting GABAergic neurons (that is, neurons that release the neurotransmitter GABA) into the brains of STXBP1 mice can reduce seizures and improved locomotion and cognition.

Dr. Wei Niu, from the University of Michigan, represented the Epilepsy Multiplatform Variant Prediction (EpiMVP) Consortium, a multi-institution, multi- researcher, collaboration aimed at trying to understand how changes in genes other than STXBP1, so-called variants of unknown significance or VUS, can have an impact on STXBP1 function. She talked about creating cell and organoid models that can be used to address this question, and that EpiMVP is building models that will be shared with the research community.

There were three talks describing approaches aimed at increasing the amount of functional STXBP1 protein as a therapy for treating the disorder. Dr. Molly Reilly, from UPenn, described how gene editing, using a tool known as CRISPR-activation, can be used to directly act on the STXBP1 gene (that is the DNA) to increase the amount of functional STXBP1 protein. Similarly, Dr. Alex Felix, also from UPenn and a member of Dr. Ben Prosser’s lab, discussed how they are using antisense oligonucleotides, or ASOs, to interact, not with DNA but with STXBP1 RNA to increase the amount of functional protein made from the RNA. This same approach is being investigated by Q-State Bioscience for STXBP1, as explained by Dr. Luis Williams. Q-State has developed a system where they can test hundreds of ASO candidates in hundreds or thousands of neurons to identify those ASOs with the best therapeutic potential.

The final two talks of the day were from Dr. Jaqueline Burre, at Weill Cornell Medicine, and Dr. Wendy Gold, from the University of Sydney. Dr Burre, who led the work that initially identified phenylbutyrate as a potential therapeutic drug for STXBP1, explained how specific mutations in STXBP1 lead to changes in other proteins associated with neurotransmission and that these changes may help explain differences in disease symptoms, and that these other proteins could potentially represent new targets for drugs. Dr. Gold discussed how her lab uses a ‘holistic approach’ in developing and testing STXBP1 AAV-viral based gene therapy products and testing novel and repurposed drugs. This involves using a variety of different techniques, such as imaging, electrophysiology, and synaptic function measures, in cells and organoids to demonstrate that a potential therapy could be a good candidate to treat STXBP1 disorder.

A major reason to have these types of meetings is not only to share knowledge but to support and encourage collaborations between researchers, which in turn will accelerate research and the development of new treatments. We are working to build and expand the STXBP1 research network. Given the enthusiastic discussions among the participants, both during and after the meeting, the 2022 Researcher Roundtable was a great success.