Drug toxicity testing utilizing human kidney on a chip
Polymyxin B (PMB) is a potent antibiotic that is used for treating life-threatening Gram-negative infections; however, PMB is considered a last line of defense due to dose-limiting nephrotoxicity. Analogs of PMB are being developed with the goal of retaining antibiotic activity while reducing drug toxicity, which is challenging to determine in preclinical animal models. In this episode, Edward Kelly and colleagues use a microphysiological system to model the human kidney proximal tubule to evaluate the toxicity of PMB and two structural polymyxin analogs. The results of this study indicate that organ on chip systems have high potential for drug toxicity screening and for elucidating mechanisms of toxicity.
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Abstract
Drug-induced kidney injury, largely caused by proximal tubular intoxicants, limits development and clinical use of new and approved drugs. Assessing preclinical nephrotoxicity relies on animal models that are frequently insensitive; thus, potentially novel techniques — including human microphysiological systems, or “organs on chips” — are proposed to accelerate drug development and predict safety. Polymyxins are potent antibiotics against multidrug-resistant microorganisms; however, clinical use remains restricted because of high risk of nephrotoxicity and limited understanding of toxicological mechanisms. To mitigate risks, structural analogs of polymyxins (NAB739 and NAB741) are currently in clinical development. Using a microphysiological system to model human kidney proximal tubule, we exposed cells to polymyxin B (PMB) and observed significant increases of injury signals, including kidney injury molecule-1 KIM-1and a panel of injury-associated miRNAs (each P < 0.001). Surprisingly, transcriptional profiling identified cholesterol biosynthesis as the primary cellular pathway induced by PMB (P = 1.22 ×10–16), and effluent cholesterol concentrations were significantly increased after exposure (P < 0.01). Additionally, we observed no upregulation of the nuclear factor (erythroid derived-2)–like 2 pathway, despite this being a common pathway upregulated in response to proximal tubule toxicants. In contrast with PMB exposure, minimal changes in gene expression, injury biomarkers, and cholesterol concentrations were observed in response to NAB739 and NAB741. Our findings demonstrate the preclinical safety of NAB739 and NAB741 and reveal cholesterol biosynthesis as a potentially novel pathway for PMB-induced injury. To our knowledge, this is the first demonstration of a human-on-chip platform used for simultaneous safety testing of new chemical entities and defining unique toxicological pathway responses of an FDA-approved molecule.
Authors
Elijah J. Weber, Kevin A. Lidberg, Lu Wang, Theo K. Bammler, James W. MacDonald, Mavis J. Li, Michelle Redhair, William M. Atkins, Cecilia Tran, Kelly M. Hines, Josi Herron, Libin Xu, Maria Beatriz Monteiro, Susanne Ramm, Vishal Vaidya, Martti Vaara, Timo Vaara, Jonathan Himmelfarb, Edward J. Kelly
