SO038A TRANSLATIONAL KIDNEY ORGANOID SYSTEM BOLSTERS HUMAN RELEVANCE OF CLINICAL DEVELOPMENT CANDIDATE

Background and Aims A major challenge in drug discovery is gaining confidence in the human relevance of pre-clinical animal studies. While human iPSC-derived organoids offer exciting opportunities to address this, concerns about applicability and scalability remain. Here, we report a high-throughput human organoid platform for assessment of kidney disease targeting compounds. Method In vitro & in vivo transplanted under athymic rat kidney capsule, differentiated organoids were characterized using single cell RNA sequencing (scRNA-Seq), NanoString, & immunofluorescence techniques. Immunofluorescence quantitative analysis of aggregated actin per in vitro organoid in a protamine sulfate (PS) podocyte injury model was used to evaluate efficacy of GFB-887, a sub-type selective, small molecule transient receptor potential canonical 5 (TRPC5) inhibitor. In pharmacokinetic studies, GFB-887 was orally administered into rats, then the presentation of GFB-887 was measured in rat plasma, rat kidney, & in vivo transplanted human organoids. In pharmacodynamic studies of transplanted human organoids, rats were co-perfused with GFB-887 & PS or orally dosed with GFB-887 prior to PS, then immunofluorescence quantitative analysis of mean synaptopodin intensity in podocytes of the in vivo transplanted organoids was used to evaluate efficacy of GFB-887. Results We confirmed platform reproducibility by scRNA-Seq and derived a NanoString panel for efficient quality control. Organoid transplantation in rats for 2 to 4 weeks promoted organoid maturation and vascularization. In functional studies, cyclosporine A (CsA), a calcineurin inhibitor clinically utilized for the treatment of nephrotic syndrome, and GFB-887, a novel sub-type selective TRPC5 inhibitor currently in clinical development, protected in vitro kidney organoids from injury. Pharmacodynamic studies with GFB-887 delivered orally to rats were also successfully performed in human transplanted organoids. Conclusion These data show how human organoids can deliver confidence in taking development candidate compounds to the clinic, fulfilling their promise to revolutionize drug discovery.