Introduction

Drug development for idiopathic pulmonary fibrosis remains challenging partly due to low translatability of animal models for pulmonary fibrosis. Human lung organoids recapitulating 3D lung structures as well as their fibrotic change are expected to be a powerful tool for improving predictivity of clinical drug effects in preclinical stages.

Objectives

We conducted a preclinical study for evaluating drug effects of a novel LPA1 antagonist, HL001, in pulmonary fibrosis models utilizing human induced pluripotent stem cell (hiPSC)-derived alveolar organoids.

Methods

Alveolar organoids were generated coculturing human lung fibroblasts and epithelial cells that stepwise induced from hiPSCs. Fibrotic phenotypes were induced by bleomycin followed by treatment with HL001. Single-cell RNA-seq analysis was performed for deeper description of drug effects.

Results

Fibrotic phenotypes in organoid including ?tissue shrinking? were ameliorated by HL001 compared to nintedanib. Single-cell RNA-seq revealed that HL001 suppressed fibrosis-associated subpopulations of fibroblasts. Expression of cellular senescence markers was also suppressed by HL001 treatment. The drug efficacy of HL001 in murine models of bleomycin-induced pulmonary fibrosis were highly compatible with that in human organoids.

Conclusions

Human stem cell-derived lung organoid models were highly useful for preclinical evaluation of drug effects. HL001 revealed significant anti-fibrotic effects both in murine models and human organoid models, which indicates high potential of HL001 as a candidate for idiopathic pulmonary fibrosis.