Genetic Rescue of Mouse Models of STXBP1 Related Developmental and Epileptic Encephalopathy in Adulthood
Abstract number :
3.046
Submission category :
1. Basic Mechanisms / 1D. Mechanisms of Therapeutic Interventions
Year :
2021
Submission ID :
1825585
Source :
www.aesnet.org
Presentation date :
12/6/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:44 AM
Authors :
Wu Chen, PhD - Baylor College of Medicine; Colleen Longley, B.S. – Baylor College of Medicine; armando Rivera, Ph.D. – Baylor College of Medicine; Alysee Michaels, B.S. – Baylor College of Medicine; Zhao-Lin Cai, Ph.D. – Baylor College of Medicine; Amy Wang, Undergradute – Baylor College of Medicine; Eugene Chao, B.S. – Baylor College of Medicine; Kevin Jin, Undergradute – Baylor College of Medicine; Alice Chen, Undergradute – Baylor College of Medicine; Sheldon Zou, Undergradute – Baylor College of Medicine; Ivanshi Ahuja, Undergradute – Baylor College of Medicine; Zain Moin, Undergradute – Baylor College of Medicine; Shawn Nguyen, Undergradute – Baylor College of Medicine; Nikita Dhar, B.S. – Baylor College of Medicine; Hongmei Chen, B.S. – Baylor College of Medicine; Joo Hyun Kim, Ph.D. – Baylor College of Medicine; Mingshan Xue, Ph.D. – Baylor College of Medicine
Rationale: Developmental and epileptic encephalopathies (DEEs) are a group of devastating pediatric neurological disorders, manifesting with aggressive seizures and significant neurological comorbidities. De novo heterozygous pathogenic variants in the gene encoding syntaxin-binding protein 1 (STXBP1) are one of most frequent genetic causes of DEEs. The abnormal brain activity during early development is believed to contribute to the pathogenesis of STXBP1 encephalopathy (STXBP1-E), presenting a great challenge for developing clinical treatments that can remain effective later in life. The current treatment options for patients with STXBP1-E are limited and ineffective. Thus, it is important to develop a therapeutic intervention that directly targets the root cause of the disease and determine the extent to which brain function can be rescued in adulthood.
Methods: Having established valid mouse models of STXBP1-E, we genetically reinstated Stxbp1 protein level in adult Stxbp1 haploinsufficient mice and examined the outcomes by health monitoring, video-electroencephalogram (EEG) recording and behavioral tests.
Results: We found that restoring Stxbp1 levels in Stxbp1 haploinsufficient mice reversed the dystonia phenotype and dramatically reduced the number of spike-and-wave discharges (SWDs) and myoclonic seizures. Furthermore, the increased anxiety-like behaviors, decreased cognitive and motor functions, and impaired innate digging and nesting behaviors were all rescued.
Conclusions: Bringing up Stxbp1 protein level in adult Stxbp1 haploinsufficient mice is able to reverse most of the phenotypes to the wildtype levels. Thus, gene replacement or activation could be an effective therapeutic method to treat STXBP1-E.
Funding: Please list any funding that was received in support of this abstract.: Citizens United for Research in Epilepsy (CURE Epilepsy Award to MX); The National Institutes of Health (R01NS100893 and R01MH117089 to MX, F30MH118804 to CL); American Epilepsy Society (Post-doctoral Research Fellowship to WC); The Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083092 to Baylor College of Medicine Intellectual and Developmental Disabilities Research Center, Neurobehavioral Core).
Basic Mechanisms