Your brain in a dish: Exploring epilepsy through electrophysiological profiling of patient-specific cerebral organoids

Afifa Saleem (1, 2), Mark Aquilino (1, 2) and Peter Carlen (1, 2)

1) Department of Fundamental Neurobiology, Krembil Research Institute, 2) Institute of Biomaterials and Biomedical Engineering, University of Toronto.

Hypothesis: 1 in 100 Canadians suffer from epilepsy, a neurological disorder characterized by repeated seizures. The standard method of treatment requires a patient to undergo therapeutic drug monitoring until an appropriately effective drug is found, which is often unique to the patient. This process takes years, puts the patient at risk of adverse effects and is only effective in up to 70% of the patient population. Herein, we propose the establishment of a novel platform, using the patient’s own cells to derive a genetically specific brain tissue model for testing, on a personalized basis, the pathophysiology and potential treatments of their intractable epileptic syndrome.

Methods & Materials: Recent advances in tissue engineering have enabled the development of cerebral organoids – 3D brain constructs that are reprogrammed from patient-specific fibroblasts or blood cells. These organoids are grown on multi-well plates and, once matured, are incubated in various epileptic and anti-epileptic conditions to assess the effectiveness of anticonvulsants. Simultaneous recordings of intracellular and local field potentials allow for the assessment of epileptiform activity.

Results: Early results with human embryonic stem cell derived organoids have shown success in observing electrically viable tissue that is responsive to convulsants. We have shown extracellular electrographic activity and whole cell intracellular activity from immature pyramidal neurons. Following the application of convulsants, 4-AP and CoCl2, slow wave activity was also evident and was faster in older organoids.

Conclusion: Preliminary results demonstrated the feasibility of the platform. Our proposed method will enable the timely determination of patient-specific anti-epileptic drug regimens, investigation of the pathophysiology with gene-editing techniques, and testing of novel therapies – thus laying the foundations for a new gold-standard for epilepsy treatment.