Epileptiform Organoids with Mutation Show Differential Responses to Anti-seizure Compounds
Abstract number :
3.201
Submission category :
2. Translational Research / 2B. Devices, Technologies, Stem Cells
Year :
2024
Submission ID :
516
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Yuling Yang, PhD – Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China
Zhicheng Shao, PhD – Institute for Translational Brain Research, Fudan University, Shanghai 200032, China
Xin Wang, MD – Zhongshan Hospital, Fudan University
Jing Ding, MD – Zhongshan Hospital, Fudan University
Rationale: Mutations in ion channel genes have long been implicated in a spectrum of epilepsy syndromes. However, therapeutic decision-making is relatively complex for epilepsies related to channelopathy, a great part of which are resistant to available pharmacological treatments. Therefore, in the present study, we employed a patient-specific organoid model with a novel SCN2A mutation to investigate the potential of utilizing organoid model as a platform for preclinical testing of anti-seizure compounds.
Methods: Electrophysiological properties of wide-type and variant Nav1.2 were determined using whole-cell voltage clamp recordings in HEK-293T cells. Patient- and healthy subjects-derived induced pluripotent stem cell lines were established by cellular reprogramming of skin fibroblasts. Cortical organoids (COs) were generated by the established protocol. Immunofluorescence and multielectrode arrays (MEA) recordings were applied to characterize COs harboring the SCN2A mutation. MEA recordings were subsequently conducted to assess drug responsiveness of the COs.
Results: The novel E512K mutation exhibited gain-of-function (GoF) effects with increased current amplitude and premature activation. The patient-derived COs displayed normal neurodevelopment of proliferation, differentiation, and layering. However, patient-derived COs showed hyperexcitability for increased frequency and amplitude of spiking, enhanced synchronous network activities, and remarkable network bursts. Moreover, patient-derived organoids exhibited differential responses to various drugs and responded well to carbamazepine.
Conclusions: Our study demonstrated that the patient-derived personalized organoids had the potential to serve as a platform for preclinical pharmacological assessment.
Funding: This study was supported by the funding from the National Key R&D Program of China (Code: 2022YFC2503802).
Translational Research