Modelling Lung Fibrosis in Human Alveolar Organoids as a Translational Platform for Drug Discovery

Background

Pulmonary fibrosis, marked by the excessive deposition of a collagen-rich extracellular matrix (ECM) within the parenchyma of the distal lung, represents the concluding pathological outcome and major cause of morbidity and mortality in several prevalent interstitial lung diseases. Amongst these, idiopathic pulmonary fibrosis (IPF), which affects ~ 5 million patients worldwide, represents the most rapidly progressive and lethal with a dismal median survival of 3-5 years from diagnosis.

Drug development for pulmonary fibrosis has been hampered by the lack of preclinical models that accurately recapitulate human lung pathophysiology and the tissue niches in which a drug candidate has to exert its therapeutic effect. Our centre at UCL, is actively addressing this by developing next-generation advanced human lung organoids, which recapitulate key features of the alveolar epithelium.

Disease-representing alveolar organoids are generated by exposure to clinically relevant stimuli, including pro-fibrotic cytokine cocktails, that mimic the molecular and cellular signals driving fibrosis in human disease, including the loss of alveolar type II (AT2) cell identity, the emergence of transitional epithelial cell states, and activation of pro-fibrotic transcriptional programs. Their tractability, scalability, and compatibility with high-resolution techniques such as single-cell RNA sequencing make them a highly valuable tool for advancing our understanding of early regenerative failure, assessment of the cellular origins of fibrotic remodelling, and the screening of candidate antifibrotic therapies in a human-relevant context.

Objectives

The key objective of this iCASE project is to validate alveolar organoids as a transformative translational platform to redefine pulmonary fibrosis research and to accelerate the discovery of breakthrough therapies. More specifically, this studentship will validate the translational fidelity of the platform by benchmarking the model against human disease signatures at the level of pathogenic cell types, transcriptional programmes, and cell–cell communication circuits using state-of-the-art single-cell RNA sequencing (scRNA-Seq) and Xenium spatial transcriptomics. To further assess their translational potential for therapeutic testing, we will benchmark the model response to standard-of-care antifibrotics and a novel PDE4B inhibitor currently in development. 

References 

Selvarajah B, Platé M, Chambers RC. Pulmonary fibrosis: Emerging diagnostic and therapeutic strategies. Mol Aspects Med. 2023 Dec;94:101227. doi: 10.1016/j.mam.2023.101227.

Mehta P, … , Chambers RC, Porter JC, Tomlinson GS. Single-cell analysis of bronchoalveolar cells in inflammatory and fibrotic post-COVID lung disease. Front Immunol. 2024 May 17;15:1372658. doi: 10.3389/fimmu.2024.1372658.

Image

Alveolar organoid image courtesy of Dr Amany Ammar (UCL Respiratory)