Resolving neuroinflammation in AD

Abstract Background Human genetics point towards a key role of microglia and microglia expressed genes like TREM2 in neuroinflammation and AD pathology, yet our understanding of microglia spatial and temporal dynamics, therapeutic directionality and translational biomarkers remains limited. Method and Results Muna Therapeutics applies structural biology, computational chemistry and human IPSC derived cell assays to develop small molecule agonists for microglial drug targets including TREM2. Introduction of human mutations allows specific drug – target interactions to be probed and has revealed novel small molecule binding pockets, enabling optimized drug design. To identify novel drug targets involved in neuroinflammation, we have built an all‐in‐human spatial transcriptomics and bioinformatics‐based discovery and validation platform. We have assessed >50 human brain samples for pathology‐induced changes in gene expression in microglia and other cells from samples with AD pathology from patients with and without cognitive impairment. This approach has revealed patterns of differentially expressed genes and pathways in brains linked to pathological hallmarks such as Ab plaques and tau tangles, as well as to resilience to the effects of these pathologies. Candidate targets and mechanisms are tested for their impact on neuroinflammation, including directionality, in humanized model systems that also enable translational biomarker discovery and validation. Conclusion At Muna Tx, state‐of‐the‐art target discovery and validation as well as structural biology and computational chemistry platforms enable microglia targeted drug discovery and can accelerate therapeutic advancement to clinical development.