Abstracts

Rationale: Syntaxin-binding protein 1 (STXBP1) encephalopathy (also known as genetic epilepsy due to STXBP1 mutations) is a rare and severe genetic epilepsy and neurodevelopmental disorder that impacts approximately 1 in 30,000 newborns. De novo heterozygous mutations in the STXBP1 gene result in impaired synaptic vesicle release and neuronal communication. Patients suffer from treatment-resistant epilepsy, profound intellectual disabilities, speech and motor impairments, behavioral issues, and increased risk of early mortality due to sudden unexpected death in epilepsy (SUDEP). Currently, no approved disease-modifying therapies exist for this debilitating disorder.


Methods: We used an Stxbp1 haploinsufficiency mouse model that exhibits key features of the human disease, including motor, cognitive, and seizure phenotypes. We assessed 3 doses of an intravenous (IV) administered adeno-associated virus (AAV) vector delivering STXBP1 to evaluate doses needed for phenotypic correction. We also utilized non-human primates (NHPs) to assess the DNA and RNA biodistribution and safety of an engineered AAV vector designed to cross the blood-brain barrier after IV administration and deliver the therapeutic gene extensively across the brain.


Results: Our findings indicate that STXBP1 supplementation through AAV gene therapy reversed disease phenotypes in a dose-dependent manner across key behavioral domains, including robust and long-lasting correction of cognition and motor deficits and correction of myoclonic and spike-wave discharge seizures, with effects observed up to one-year post-treatment. In NHPs, an engineered AAV vector delivering STXBP1 (CAP-002 drug product) achieved widespread DNA, RNA, and protein distribution in up to 70% of neurons brain-wide at low to moderate doses. This drug product is well tolerated and has reduced liver targeting compared to traditional AAV9 vectors, enabling lower dosing and a broader therapeutic window.


Conclusions: These studies demonstrate potential for a first- and best-in-class, disease-modifying gene therapy for genetic epilepsy due to STXBP1 mutations. The CAP-002 gene therapy achieved levels of STXBP1 protein expression brain-wide in NHPs that were sufficient to produce meaningful and sustained phenotypic correction in the mouse model, highlighting the potential for significant clinical benefit. Capsida's STXBP1 program has entered IND-enabling studies for STXBP1 encephalopathy.




Funding: The NHP work was supported by Capsida Biotherapeutics, and the murine work was supported in part by a sponsored research agreement from Capsida Biotherapeutics to Baylor College of Medicine and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (P50HD103555 to Baylor College of Medicine Intellectual and Developmental Disabilities Research Center, Neurovisualization Core and Neurobehavioral Core). M.X. is a Caroline DeLuca Scholar.