STARR, ESCO, and building the STXBP1 momentum

Physics. When I tried to summarize the STXBP1 Summit in Colorado on my way back, I got stuck with the concept of momentum. Lots of things are happening in the world of STXBP1 disorders, but the most important thing is momentum, defined by Merriam-Webster as strength or force gained by motion or by a series of events. Buoyed by two natural history studies, STARR and ESCO, things are certainly in motion. Here are a few take-aways from the STXBP1 Summit.

Perspective. As with many other blog posts about scientific meetings or conferences, let me state that this post is not meant to provide a complete overview. Quite the opposite, I wanted to focus on a few aspects of the STXBP1 Summit that was held on July 21-22 in Westminster, Colorado. First, I wanted to thank the Foundation and all the families for such a professional meeting. Having been part of the STX Community from its inception, I have seen this meeting become more and more impressive every year. If you had asked me five years ago, I probably would have told you that such a meeting would likely never happen given that STXBP1 was largely unknown. But things have really changed, and I stand by last year’s statement that STXBP1 disorders is the singular neurodevelopmental disorder with the fastest growing knowledge.  

NHS. Being part of a Natural History Study (NHS) feels interesting and I had an “aha moment” when the word momentum popped up in my mind. A NHS is somewhat slow on purpose – it is not a breakthrough research effort that keeps you on your toes, but it is a gentle, irresistible push into a new direction. In the case of the two STXBP1 Natural History Studies, STARR in the US and ESCO in Europe, the direction is towards making STXBP1 measurable in new and standardized ways that will allow us to better define the disorder with the goal of more accurate prediction and treatment strategies. The days of case reports and n-of-one experiences are over – the discussion is shifting towards our experience with standardized outcome measures and whether Bayley raw scores or growth scale values (GSV) are more useful. 

First steps. It feels like something has finally started to move, initially slow and imperceptible, but with sufficient mass to make it basically unstoppable. I had the image of a massive stellar body on my mind when I was asked the question on when our Natural History Studies will eventually stop. I was trying to find words to explain that we have crossed a threshold where sufficient momentum is gathered to make the generation of knowledge surrounding STXBP1 unstoppable. With putting numbers and precision into STXBP1, we will have sufficient questions for the next decade to come, far beyond what is needed for initial trial readiness. We have already seen some initial glimpses of what these questions might look like: we have seen that gross motor scores in individuals with STXBP1-related disorders seem to converge at the age of 4-5 years despite vast differences between individuals in early childhood. Will this observation hold true, and can we use this for trial design? We have observed unusual trajectories of the STXBP1 tremor. Is there a way to predict its severity and impact on could this be used as a biomarker? Questions like this have direct clinical relevance in addition to adding to trial readiness and we will be able to unfold layer after layer once we have the initial set of data.  

Innovation. In addition to putting STX into numbers, I tried to emphasize another aspect during my presentation in Colorado. Researching trial readiness and natural history in STXBP1 is not just an exercise in filling in gaps. Quite the opposite, it puts us to the very forefront of discovery by turning some of the obstacles into advantages. STXBP1 is a difficult condition to conceptualize: we see dynamic changes in seizure patterns and significant differences even between individuals with identical genetic changes. However, these features of STXBP1-related disorders present a unique opportunity to rethink how we approach neurodevelopmental disorders more broadly. We presented several novel methods where we merged disease reconstructions with data analysis methods based on artificial intelligence that allow us to make STXBP1 predictable using methods based on seizure forecasting and virtual clinical trials. This strategy is nothing new – pressure leads to innovation. It was just a matter of time that the challenges of the complex STXBP1 natural history made us develop new methods. And as we saw in Colorado last weekend, many groups have answered this call and are working on novel and creative ways to use the enormous momentum that the STXBP1 field has developed.  

Ingo Helbig is a child neurologist and epilepsy genetics researcher working at the Children’s Hospital of Philadelphia (CHOP), USA.