Artikel
Translational modelling of gene therapy for pharmacoresistant epilepsy in human brain slice cultures
Humane Hirnschnitt Kulturen als translationales Modellsystem zur Untersuchung gentherapeutischer Ansätze für pharmakoresistente Epilepsie
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Veröffentlicht: | 25. Mai 2022 |
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Gliederung
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Objective: Investigations of precision medicine related approaches for human CNS disease mostly rely on animal models or cell culture systems including human induced pluripotent stem cell technology. However, it frequently remains elusive how well such data translate to the native human brain. Devising strategies based on live human CNS tissue could offer a promising step toward bridging this gap.
Methods: We recently optimized a model system based on human brain slice cultures, derived from access tissue of neurosurgical procedures. We demonstrated preservation of complex neuronal cytoarchitecture and of electrophysiological properties of human neurons over several weeks in vitro and achieved efficient viral transduction of neurons within cultures. This model system has implications for a broad spectrum of translational studies including dissection of pathophysiological mechanisms underlying human CNS disease and therapeutic screening.
Results: The success of such studies will depend on the ability to genetically target human cells with subtype specificity. Taking advantage of different AAV serotypes in combination with various promoters we are increasingly matching these requirements. We are now working toward modelling of neurological disease such as intractable epilepsy and severe epileptic encephalopathy. In a second line of experiments we are investigating feasibility of new gene therapeutic strategies to revert pathological states within the context of human cortex and hippocampus.
Conclusion: Human brain slice cultures in combination with state-of-the-art technology such as targeted genetic modification, high-resolution imaging, patch-clamp and multi-electrode-array electrophysiology are proposed as a platform for investigation of human CNS disease and for probing new therapeutic concepts. The focus of interest of ongoing studies includes plasticity mechanisms of human neurons, the impact of epilepsy-causing ion channel mutations on cortical circuitry and progressively optimized new approaches for modulation of epileptic network activity.