A Patient-Specific hiPSC Model of Nilotinib-Induced Peripheral Artery Disease Pharmacogenomics

Peripheral artery disease (PAD), a subtype of atherosclerosis, affects approximately 8.5 million people in the United States. PAD confers a three-fold increased mortality risk and is comparable to coronary heart disease in increased risk for mortality, myocardial infarction, and ischemic stroke. Nilotinib is a tyrosine kinase inhibitor (TKI) increasingly used to treat chronic myeloid leukemia (CML).While nilotinib successfully treats CML, a common and serious side effect (noted in 26% of individuals) is development of PAD even in patients without pre-existing risk factors. A subset of patients with nilotinib-induced PAD (N-PAD) require invasive interventions and, in some cases, amputation. Currently no tools exist to understand the mechanism of -PAD or preemptively identify which patients may susceptible to this adverse effect. Consequently, patients are identified only after they have developed irreversible complications. Human induced pluripotent stem cells (hiPSCs) constitute a unique and efficient system with which to study interindividual variability in adverse drug reactions. hiPSC derivatives have previously been shown to recapitulate patient-specific susceptibility to both drug-induced and genetic phenotypes. Because hiPSC derivatives are genetically identical to the patients from whom they are derived, they are well-suited to the study of N-PAD pharmacogenomics and can be used to both identify and validate causal variants. These variants will then inform clinical genetic screening as well as mechanistic understanding of N-PAD. In this study we will develop an in vitro model of N-PAD. In Aim 1 we will functionally and biochemically characterize response to nilotinib exposure in hiPSC-derived endothelial and vascular smooth muscle cells from patients with and without N-PAD. We predict that these cells will recapitulate patient-specific susceptibility to N-PAD and provide a model with which to probe the mechanism of this side effect. In Aim 2 we will assess the gene expression response to nilotinib in hiPSC-derived cells from patients with and without N-PAD in order to identify novel variants, which will then be validated with genome editing. Accomplishment of these aims will establish an in vitro model for PAD and atherosclerosis in addition to elucidating the mechanism of N-PAD and identifying relevant variants for clinical screening.