Disease mechanism and genetic therapy for a pathogenic STXBP1 variant

PROJECT SUMMARY STXBP1 encodes syntaxin-binding protein 1, an essential protein for presynaptic neurotransmitter release. Patients with heterozygous pathogenic variants in STXBP1 are characterized by intellectual disability, epilepsy, movement, and psychiatric disorders, which are collectively termed STXBP1-encephalopathy (STXBP1-E). STXBP1-E is among the most common and severe forms of developmental and epileptic encephalopathy. The current treatments at best only alleviate individual symptoms without targeting the underlying genetic defect. Haploinsufficiency has been clearly identified as the disease mechanism for patients with truncating variants, which is supported by multiple in vivo mammalian models that recapitulate neurological phenotypes of patients. In contrast, the mechanism of action for missense variants, which make up 48% of the STXBP1-E patient population, remains unclear, in part due to the lack of in vivo mammalian models with construct and face validity. This leaves a critical knowledge gap in understanding the disease mechanism and developing mechanism-based genetic therapies. Thus, there is a critical need to establish a mouse model of STXBP1 missense variants to address this gap. To this end, the applicant focused on one of the most common and understudied missense variants in STXBP1 and has established a knock-in mouse model that recapitulates all key aspects of disease including epilepsy and impaired motor and cognitive functions. The goal of this project is to use this mouse model to understand the molecular and synaptic mechanisms (Aim 1) and determine the efficacy of an adeno- associated virus (AAV)-based gene therapy in rescuing the neurological dysfunctions (Aim 2). The applicant will use genetic manipulations in combination with various techniques including biochemistry, electrophysiology, optogenetics, behavioral assays, and electroencephalography (EEG) recordings. The proposed research is expected to elucidate how a common missense variant contributes to neurological phenotypes in a mouse model of STXBP1 encephalopathy and determine the potential of gene therapy as a therapeutic option. Furthermore, this project is designed to prepare the applicant for a career as an independent scientist in research and development and furthers the applicant’s long-term goal of performing gene therapy research to reduce the burden of neurological disease for all people. The Sponsor, Dr. Mingshan Xue, has a strong track-record of successful trainees and his lab conducts impactful research using mouse models of neurodevelopmental disorders to discover disease mechanisms and genetic therapies to treat the disease. Furthermore, the collaborative training environment of both Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute provides state-of-the-art technology cores, experts in the field of neurological disorders, and a central location in the Texas Medical Center that facilitates the success of the project and training of the applicant.