Advances in STXBP1 encephalopathy research and translational opportunities

STXBP1 encephalopathy (STXBP1-E) is a rare neurodevelopmental disorder that includes epilepsy; it is caused by de novo STXBP1 mutations. In clinical settings, pharmaceutical interventions to treat STXBP1-E predominantly concentrate on seizure control. However, effective treatments for seizure recurrence, treatment resistance, and common comorbidities remain scarce. Patients with STXBP1-E display a wide range of pathogenic variations that manifest as loss-of-function, gain-of-function, or dominant-negative effects. However, recent studies have primarily investigated the pathogenic mechanisms resulting from loss-of-function mutations using STXBP1 haploinsufficiency models. This approach fails to accurately assess the impact of disease-causing mutations. Moreover, to evaluate new syntaxin-binding protein 1 (STXBP1)-targeting drugs, novel models that incorporate disease-causing mutations or even the genetic backgrounds of patients are needed. Here, we discuss the clinical symptoms of STXBP1-E and the relationship between this disorder and STXBP1 mutations. We also review recent progress toward understanding the biological function of STXBP1 and its deficiency-induced cellular defects. We then discuss recent discoveries concerning the pathogenesis of STXBP1-E and the limitations and challenges associated with the current research model. Additionally, we underscore the value of leveraging stem cell technology to study the pathogenic mechanisms of STXBP1-E, and review stem cell transplantation as a potential approach for treating this disorder. We also discuss potential future research directions that need to be resolved.