Development of pharmacokinetic assays utilizing an organ-on-chip model of the human kidney proximal tubule

Project Summary The proposed application focuses on the development of a plug and play living human kidney on chip for assaying secretion of drug candidates by the kidney proximal tubuleOnce commercializedthe chip will enable drug developers to better screen pre clinical drug candidates for nephrotoxic side effectsThis stands to reduce the high attrition rate of drugs in clinical trialsgiven that aboutfail because of nephrotoxicityand would make drug development fastermore cost efficientand saferConventional preclinical models are of limited use for assessing tubular secretionIn animal modelstransporter proteins in the kidney epithelium differ significantly from those present in human kidneyD in vitro modelseven when using human cellsfail to provide appropriate culture conditions that enable appropriate cell functionThe proposed kidney chip will leverage the commercially available Nortis organ on chip platform that is currently in use for a number of organ applicationsincluding a first generation kidney model that contains a human kidney proximal tubuletissue engineered from primary cellsIn order to make the kidney chip useful for wide spread use in pre clinical assessment of renal secretionsubstantial improvements are necessaryA marketable product requires a stable source of cells with sufficient performanceprecision delivery of compounds to the basolateral side of the proximal tubule in the chipand precise fluid sampling from the chipFurtherchips arriving pre loaded with living proximal tubules will represent a significant value increase to the customerPhase I of the project will aim to demonstrate that specific transporter proteins OATand OCTwhich are crucial to renal secretionfunction correctlyPhase I AIMTo prove thisproximal tubules in the chips will be exposed to specific substratesadefovir for OATcimetidine for OCTin conjunction with specific inhibitors of these transporterspara aminohippurate for adefovir and metformin for cimetidineThe cells used for growing the tubules will be derived from an immortalized human kidney proximal tubule cell line that has been shown to express OATand OCTin the correct cell compartments when cultured in the Nortis chipPhase I AIMwill be to implement chip features for precise sampling of microliter scale fluid volumes upstream and downstream of the tubulewhich is required for assessing the secretory flux parameter termed the permeability surface area productPaDuring Phase II the chips will be equipped with features for tight control of compound delivery to the basolateral side of the proximal tubulePhase II AIMThe following aimPhase II AIMwill then focus on qualifying assays of kidney proximal tubule secretory clearance for OATand OCTwith sufficient statistical power to establish robustness and reproducibilityPhase II AIMis designed to establish that living kidney chips can be shipped to customers with uncompromised assay performancewhich will be validated by an independent laboratoryOnce fully developed and commercialized the proposed kidney chip might be suitable for applications beyond the pharmaceutical sectorsuch as environmental health andampsafetyprecision medicineand regenerative medicine Project Narrative Nephrotoxicity is a major cause of drug attrition during pre clinicalclinicaland post approval stages of developmentA widely available kidney on chip system will enable more predictive preclinical screening of drug candidatesOnce commercializedthe kidney on chip system will reduce the need for animal testingwill make drug development more time and cost efficientand will increase the success rate of clinical trials