GAD autoantibody associated epilepsy (GADAE) is a condition in which autoantibodies to glutamic acid decarboxylase (GAD) are associated with seizures. Anti-seizure medications and surgery do not reduce seizures in GADAE and current treatments work to dampen down the immune system, but these are often ineffective. Therefore, patients remain disabled with frequent seizures. To improve treatments, we need to understand the pathological mechanisms underlying this condition to identify effective therapeutic targets.

The exact pathological mechanisms underlying GADAE are unknown. It remains unclear as to whether GAD autoantibodies are directly pathogenic and there is some evidence to suggest that T cells are important in mediating the disease. Studies from animal models have been inconclusive and no studies to date have looked at the effects of GAD-specific autoantibodies or T cells on human tissue. Our research aims to ultimately investigate the immunopathogenesis of GADAE by creating a human cell-based model of GADAE from human induced pluripotent stem cells (iPSCs), adding GAD-specific antibodies and/or T cells and analysing their effects on cellular function. This project will provide crucial preliminary work for this.

Initially, we have performed single cell ribonucleic acid sequencing on the cerebrospinal fluid of GADAE patients as this can identify and characterise enriched immune cell populations in detail. We will analyse this data and through comparison to controls we will gain insight as to what specific immune populations are likely important in mediating GADAE, thereby influencing which specific immune cells should be generated. We can also derive GAD-specific B and T cell receptor sequences, and this can be used to create GAD-specific antibodies and T cells in the future. In conjunction, we will also create a cell-based model of GADAE by deriving patient’s iPSCs into co-culture of human cortical neurons and microglia, an important immune regulatory cell in the brain.