High throughput human systems for target discovery and validation in tissue fibrosis

Lead Supervisor: Dr Andrew Lewis

Co-supervisor: Dr Chris Toepfer

Commercial Partner: GSK

Tissue fibrosis represents a major unmet medical need, contributing to major causes of death and disability including idiopathic pulmonary fibrosis, metabolic dysfunction-associated steatotic liver disease, chronic kidney disease, and heart failure with preserved ejection fraction. Despite this substantial disease burden, only two partially effective antifibrotic drugs exist, which slow rather than reverse fibrosis, with no approved specific therapies for cardiac, hepatic, or renal fibrosis. This gap stems from translational challenges: mouse models may not recapitulate human-specific fibrotic pathways, traditional cell culture systems cannot recapitulate the multicellular interactions driving fibrosis, and progressive matrix remodelling characteristic of fibrosis is poorly modelled in two-dimensional systems.

This MRC iCASE Oxford-GSK collaboration aims to develop and validate a novel bioprinted three-dimensional human induced pluripotent stem cell-derived tissue platform to identify and test therapeutic targets for fibrosis. The project will utilise engineered cardiac microtissues incorporating cardiomyocytes, cardiac fibroblasts, macrophages, and endothelial cells in physiological ratios to model both genetic and environmental drivers of fibrosis. Through comprehensive secretome profiling, single-cell transcriptomics, and CRISPR-based functional validation, the project will systematically identify core fibrotic mediators co across organ systems whilst distinguishing tissue-specific modifiers.

The four-year programme encompasses platform development and secretome characterisation in year one, target discovery and cross-tissue validation in year two, followed by advanced validation and clinical translation in years three and four. The project will exploit Oxford's expertise in cardiac organoid/genetic technology and spatial transcriptomic atlases of human fibrotic tissues, combined with GSK's capabilities in high-throughput screening, compound libraries, and multi-organ fibrosis models.

For GSK, this collaboration provides access to a sophisticated human tissue modelling technology that addresses the translational failures hindering fibrosis drug development. The platform enables systematic target discovery using human-relevant systems, potentially identifying therapies applicable across multiple organ systems. The standardised 384-well format will integrate with existing drug discovery infrastructure. For Oxford, the partnership offers access to multi-organ transcriptomic datasets, access to proprietary compound libraries for target validation, and potential pathways for clinical translation of targets.

Expected deliverables include a comprehensive secretome atlas of cardiac fibrosis, validated therapeutic targets with CRISPR and small molecule confirmation, standardised protocols for high-throughput tissue production reproducible across laboratories, patent filings on novel targets and screening methodologies, and two to three high-impact publications. The platform technology developed will be applicable to hepatic, pulmonary, and renal fibrosis, establishing a new paradigm for human-first drug discovery in complex diseases. This aligns closely with MRC's remit to improve human health through world-class medical research, addressing a major cause of morbidity and mortality whilst developing innovative technologies for therapeutic discovery.

Apply using course: DPhil in Medical Sciences