Human Cortical Organoids with a Novel SCN2A Variant Exhibit Hyperexcitability and Differential Responses to
Yuling Yang1, Yang Cai1, Shuyang Wang1
1Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Abstract:
Mutations in ion channel genes have long been implicated in a spectrum of epilepsy syndromes. However, therapeutic decision-making is relatively complex for epilepsies associated with channelopathy. Therefore, in the present study, we used a patient-derived organoid model with a novel SCN2A mutation (p.E512K) to investigate the potential of utilizing such a model as a platform for preclinical testing of anti-seizure compounds. The electrophysiological properties of the variant Nav1.2 exhibited gain-of-function effects with increased current amplitude and premature activation. Immunofluorescence staining of patient-derived cortical organoids (COs) displayed normal neurodevelopment. Multielectrode array (MEA) recordings of patient-derived COs showed hyperexcitability with increased spiking and remarkable network bursts. Moreover, the application of patient-derived COs for preclinical drug testing using the MEA showed that they exhibit differential responses to various anti-seizure drugs and respond well to carbamazepine. Our results demonstrate that the individualized organoids have the potential to serve as a platform for preclinical pharmacological assessment.
Insights
Patient-derived organoids with a novel SCN2A mutation model epilepsy. These organoids show drug responses, highlighting their potential for preclinical anti-seizure compound testing.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Epilepsy syndromes are linked to ion channel gene mutations.
- Therapeutic strategies for channelopathy-associated epilepsies are complex.
- A novel SCN2A mutation (p.E512K) was identified.
Purpose of the Study:
- To investigate patient-derived organoids as a platform for preclinical anti-seizure drug testing.
- To characterize the functional effects of a novel SCN2A mutation.
- To assess drug efficacy using an individualized organoid model.
Main Methods:
- Generated patient-derived cortical organoids (COs) with a novel SCN2A mutation.
- Performed electrophysiological analysis of the variant Nav1.2 channel.
- Utilized multielectrode array (MEA) recordings for network activity assessment.
- Tested differential responses to anti-seizure drugs in patient-derived COs.
Main Results:
- The SCN2A variant (p.E512K) demonstrated gain-of-function effects with increased current and premature activation.
- Patient-derived COs exhibited normal neurodevelopment.
- MEA recordings revealed hyperexcitability, increased spiking, and network bursts in patient-derived COs.
- Patient-derived COs showed varied responses to anti-seizure drugs, with a positive response to carbamazepine.
Conclusions:
- Individualized organoids serve as a viable platform for preclinical pharmacological assessment.
- This model accurately reflects disease phenotype and drug response.
- Novel SCN2A mutation impacts ion channel function, leading to epilepsy characteristics.
