Herophilus announced the publication of “Neuroimmune Cortical Organoids Overexpressing C4A Exhibit Multiple Schizophrenia Endophenotypes” in bioRxiv, the preprint server for biology. The findings further demonstrate the emerging role the neuroimmune axis may play in the development of schizophrenia and in providing a platform for schizophrenia drug discovery. The paper reports results from an ongoing research collaboration between Herophilus and Cerevel Therapeutics launched in December of 2021.

The starting point for the research was Herophilus' proprietary NICO™ (neuro-immune cerebral organoid) model which allows the study of neuroimmune interactions between microglia, neurons, and astrocytes in a realistic human tissue-like context. The NICO™ model is a component of the Herophilus Discovery Engine, which powers the use of human-derived, complex in vitro experiments for scaled, AI-driven drug discovery. There is a growing body of evidence implicating the neuroimmune system in the origin of schizophrenia and other complex brain diseases.

Recent population-based genetics studies showed that higher levels of C4A correlate with increased schizophrenia risk. C4A is a key molecule of the complement pathway that is implicated in microglia-driven synaptic pruning. Thus, overexpression of C4A in the Herophilus NICO™ system was used to study the impact that a schizophrenia risk gene may have on the neuroimmune response.

The C4A NICOs were extensively profiled across several readouts of inflammation and neuroimmunological dysfunction. Several endophenotypes, biological markers of a disorder suspected to be part of the causal chain between genetic factors and ultimate patient symptoms, were observed in the C4A neuroimmune organoids. These included: modulation of inflammatory genes, release of secreted cytokines, and increased uptake of synapses by microglia.