About

Kidneys are critical for the elimination of many drugs and metabolites via the urine, filtering waste and maintaining proper fluid and electrolyte balance. Proximal tubule epithelial cells are the main driver of renal transport and secretion of xenobiotics, making them susceptible to drug-induced kidney injury, which can be a dose-limiting factor in pharmacotherapy and potentially lead to organ failure. The clinical incidence of drug-induced kidney injury is in the range of 14-26% (Awdishu et al, BMC Nephrology, 2017). There is a need for more predictive, human-relevant models to screen for nephrotoxicity liabilities during the drug discovery and development process. In addition, mismatch between preclinical and clinical readouts warrant additional investigation using in vitro proximal tubule models from different species.

The IQ MPS Affiliate (IQ MPS) and the Critical Path Institute (C-Path) seeking information and proposals from developers of novel renal proximal tubule MPS. These novel renal proximal tubule MPS should ideally have a clear mechanistic rationale that not only recapitulates critical renal functions, such as active transporter-mediated uptake, but also demonstrates improved clinical predictivity for key toxicological responses. In addition, platforms that enable meaningful cross-species comparisons and improve our understanding of species-specific and human-relevant responses are of strong interest. While a single model capable of addressing all toxicological endpoints would be desirable, it is not the primary objective. Emphasis will be placed on endpoint-specific predictivity of clinical outcomes, translational relevance across species, and demonstrated utility in supporting drug discovery and development decisions, as these factors will be most critical for future adoption of these systems.

Technical Requirements

For the purposes of this RFI/RFP, MPS refers to models that encompass two or more of the following: multi-cellular/multi-layered tissue, microfluidics, stretch, derived of primary or stem cell-derived cells, or include an immune cell component. Specifically, this project seeks to investigate models such as organoids, microtissues, organs-on-a-chip, or a combination thereof.

The renal proximal tubule MPS would ideally be viable and amenable to multi-day, repeated apical and/or basal dosing and exhibit appropriate barrier function and key ADME-related gene expression, localization, and activity (e.g. OAT1, OCT2 and megalin/cubulin).