The STXBP1 Disorders Foundation just had its yearly scientific investigator retreat July 17-20, 2024. Here are some of the jaw-dropping advancements in drug discovery!

Ben Prosser, the Director of ENDD program at CHOP, showed data that an ASO scan of the entire sequence of STXBP1 has found two ASO sites in 3'UTR that are capable of increasing protein expression in iPSC-derived neurons when exposed to the appropriate ASO. Zach Grinspan showed data on the drug repurposing candidate, phenylbutyrate that was initially discovered in a variant-humanized worm, appears to be effective in the clinic. Sagi Gidali also showed results from another drug repurposing screen in worms that found activity in nicotinamide mononucleotide (NMN) is also having therapeutic benefit in another child with a pathogenic variant in STXBP1.

Tissue type for pathogenicity and therapy may need to take into account the cellular "milieu" - the neighboring cells that can have profound influence. Intriguingly Amparo Roig Adam showed in single-cell Differential Gene Expression (DGE) studies that astrocytes have more significant gene expression changes in STXBP1 heterozygotes when compared to the relative changes in GABAnergic and gluatmatergic neurons. Although it well established protein levels of STXBP1's main binding partner, syntaxin drop, in heterozygotes, the mRNA levels of this protein biomarker do not change in these DGE studies. Intriguingly, statmin1 was observed as having decreased expression which may lead to cell death as it's related biomaker, statmin2, does in ALS models. Another potential biomarker of STXBP1 pathogenicity, Caroline Pearson showed us that organoids, which containing multiple cell types were able to show in heterozygotes that they are consistently smaller. Further, in MEA's on these cells, they have reduced synchronous activity.

On the AAV therapy development front, Beverly Davidson gave us detail on new capsids for neuronal targeting (AAV-DB-3) have high specificity. Suresh Poda at Encode Therapeutics talked about their novel promoters for high expression in AAV cargo in neurons. And finally Swati Tole and Alberto Lopez at Capsid described a novel capsid that targets neurons and avoids liver. This, and their amenability for sufficient flux across brain capillaries and efficient penetration of the Blood Brain Barrier (BBB), has the potential to be an injectable therapy. This latter claim of injectability caused a bit of controversy, as other developers of AAV therapies suggested intracranial (ICV) is likely to be the only successful route of administration. So time will tell if Capsida's technology can truly achieved this goal of an injectable that readily crosses the BBB, transfect target neurons, and all the while achieve nontoxic effects on other tissues, namely unwanted liver and kidney transduction and toxicity.

Other shoutouts of the meeting that stood out for me wereWendy Gould for use of multiomics technologies to find key biomarkers,Peter Galer for identification of EEG biomarkers in STXBP1 patients,Jay Pathmanathan at Beacon for describing machine learning methods to create quantifiable EEG biomarkers,Ganna Balagura for appreciating STXBP1's role in Gut-Brian axis in controlling GLP-1 secretion from L cells,Juliet Knowles for suggesting nortriptyline from SYNGAP1 synaptopathies may also be therapeutic for STXBP1 pathologies, and Ingo Helbig for detailing the clinical trials preparedness that is getting matured in the STARR program.