537. Bridging the translational gap in psychiatry using a multimodal multi-omics collaboration: the consortium for preclinical psychiatric research

Abstract

Abstract Background There is a critical need to change the treatment paradigm for mental disorders by developing interventions that are able to target specific clinical components, alter the disease course and are not merely palliative in intent. A key strategy towards this goal is to focus research on causal pathways in mental disordersPMID:35026139. However, despite considerable advancesPMID:27144355, 38104575, 36801618, connecting associational findings with causal pathways remains elusive. This is largely attributable to the absence of clinically useful biomarkers, assayable structural pathology and the technology to directly investigate putative molecular pathologies in the human brain. Moreover, disorder heterogeneity with considerable inter- and intra-individual variation of symptom profile across the disease course suggests diverse underlying disease processes. These challenges have forced attention on preclinical models but there is widespread recognition of major unmet translational needs which stymie drug target identification and validation for mental disorders. These gaps have prompted calls to integrate and synthesis information from diverse preclinical modelsPMID: 39245692and that to address this requires a collaborative multi-disciplinary approach uniting preclinical and clinical research and lived experience. We describe here the creation of an international collaborative network of preclinical psychiatric research, the Consortium of Preclinical Psychiatric Research (CPPR)PMID: 41315813. We then describe how the CPPR will use a multimodal multiomics pipeline to probe schizophrenia by synthesising information from diverse preclinical models and integrating this with clinical data to build a data commons globally accessible and interrogable through AI and machine learning approaches. We propose this will accelerate understanding of causal pathways leading to schizophrenia and subsequently other mental illness and identification of putative biomarkers and novel treatment targets. Aims & Objectives 1. To establish an international consortium of preclinical psychiatric research incorporating the full spectrum of preclinical psychiatric models including animal, cell and stem cell, clinical biological samples, imaging data and human post-mortem brain tissue. 2. With schizophrenia as an exemplar to use a multimodal multiomics pipeline to generate putative biomarkers and novel drug targets. 3. To create a globally accessible data commons of harmonised "omics" data integrated with clinical data sets. Method Animal prefrontal cortex and hippocampus samples from 544 animals from 17 models, 34 cell lines, 705 human post-mortem dorsolateral prefrontal cortex and hippocampus tissue samples and 200 clinical plasma samples covering schizophrenia and healthy controls will undergo proteomic (Orbitrap Astral mass spectrophotometry / Seer Proteograph XT) and direct RNA long-read transcriptomics (Oxford Nanopore Technologies ONT) for epigenomic and transcriptomic data. Analysis and synthesis of data will be undertaken with Australian Biocommons through the open-source Gen3 platform. Results The CPPR was established in 20246 with over 50 researchers and 14 institutions. Deep phenotyping of >1450 distinct preclinical and clinical samples relevant to schizophrenia is being undertaken to create a comprehensive and detailed map of putative pathways involved in schizophrenia. Discussion & Conclusions The CPPR presents a novel approach to bridge the translational gap in psychiatric disorders. It will create a template using schizophrenia that can be applied across mental disorders and herald a new path for fast-tracking putative biomarker and drug target identification.