Identification Of a Therapeutic Threshold For AAV-STXBP1 Gene Therapy in a Rodent Model of STXBP1 Developmental & Epileptic Encephalopathy
Brief intro:
- Author: Nicholas B. Gallo, John W. Annand, Pete Clarner, Brian Harvey, Elena Morozova, Christian Ehrenfels, Ting Jiang, Long Yuan, Samneet Kashyap, Xiaodong Lu, Jinkuk Choi, Jennifer Zoll, Anh Nhu, Ashton Brennecke, Purvish Patel, Davide Gianni, Edward Guilmette, Sarah Geisler, Adam Sheehy, Kevin Ghaemi, Sam Benezra, Ayan Ghoshal, Yuqing Liu, Thomas Carlile, Shaolong Cao, Fergal Casey, Samir Koirala, Sijia Wu
- Journal: Molecular Therapy
- Doi: https://www.doi.org/10.1016/j.ymthe.2026.03.027
- Publication Date: 2026/3/24
Abstract
STXBP1-related developmental and epileptic encephalopathy (STXBP1-DEE) is a debilitating genetic epilepsy disorder caused by heterozygous loss of function mutations in the STXBP1 gene. Gene supplementation therapy using adeno-associated virus (AAV) technology is an attractive approach to restore functional STXBP1 expression in the central nervous system (CNS) and improve STXBP1-DEE symptoms. Currently, there is no clear clinical data or human evidence defining a therapeutic threshold of AAV-mediated STXBP1 expression. Here, we describe an approach to define this therapeutic threshold using Stxbp1+/- mice and correlating neuronal transduction with phenotypic improvement. Our AAV-STXBP1 vectors dose-dependently rescued disease-associated phenotypes, with ≥44% cortical neuronal transduction needed for phenotypic improvement, setting a potential therapeutic threshold. Long term analysis demonstrated that STXBP1 transgene expression in the brain is durable up to one-year. Finally, a mass spectrometry assay capable of simultaneous detection of STXBP1 and syntaxin-1 (STX1) in human cerebrospinal fluid (CSF) is presented that may enable translation into a clinical grade assay. Altogether, our results identify a potential therapeutic threshold for gene therapy expression in key brain regions for STXBP1-DEE and advance the possible utility of STXBP1 and STX1 in CSF as key protein biomarkers, thereby supporting further development of AAV-based gene supplementation strategies for this disorder.
About PackGene
PackGene Biotech is a world-leading CRO and CDMO, excelling in AAV vectors, mRNA, plasmid DNA, and lentiviral vector solutions. Our comprehensive offerings span from vector design and construction to AAV, lentivirus, and mRNA services. With a sharp focus on early-stage drug discovery, preclinical development, and cell and gene therapy trials, we deliver cost-effective, dependable, and scalable production solutions. Leveraging our groundbreaking π-alpha 293 AAV high-yield platform, we amplify AAV production by up to 10-fold, yielding up to 1e+17vg per batch to meet diverse commercial and clinical project needs. Moreover, our tailored mRNA and LNP products and services cater to every stage of drug and vaccine development, from research to GMP production, providing a seamless, end-to-end solution.
