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

> **NIH NIH F31** · NORTHWESTERN UNIVERSITY · 2021 · $41,293

## Abstract

PROJECT SUMMARY
Peripheral artery disease (PAD), a subtype of atherosclerosis, affects approximately 8.5 million people in the
United States. PAD confers a three-fold risk of all-cause mortality and is comparable to coronary heart disease
in increased risk for mortality, myocardial infarction, and ischemic stroke. Nilotinib is a highly effective treatment
for chronic myeloid leukemia (CML) but causes pathologic changes in blood pressure consistent with PAD in
26% and 35% of patients on first- and second-line nilotinib respectively. PAD occurs even in nilotinib-treated
patients without pre-existing cardiovascular risk factors and in some cases is sufficiently severe to necessitate
amputation. Currently no tools exist to understand the mechanism of nilotinib-induced PAD (N-PAD) or
preemptively identify which patients may susceptible to this adverse effect, meaning that susceptible 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, including cardiomyocytes, endothelial cells, and vascular smooth muscle cells,
have previously been shown to recapitulate patient-specific susceptibility to both drug-induced and genetic
phenotypes. Because hiPSCs and their derivatives are genetically identical to the patients from whom they are
derived, they are well-suited to the study of the pharmacogenomics of N-PAD 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 cells and vascular
smooth muscle cells from patients with and without N-PAD. We predict that these cells will recapitulate patient-
specific susceptibility to nilotinib treatment and provide a model with which to probe the mechanism of this effect.
In Aim 2 we will assess the gene expression response of hiPSC-derived cells from patients with N-PAD to
nilotinib in order to identify novel variants, which will then be validated through CRISPR/Cas9 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. Additionally, the
proposed project will provide a platform for the applicant's predoctoral training and allow for the development of
expertise in experimental design and analysis, a broad repertoire of technical skills, and expertise in
computational pharmacogenomics approaches while also enhancing clinical and professional skills.

## Key facts

- **NIH application ID:** 10128199
- **Project number:** 5F31HL151160-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Emily Pinheiro
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $41,293
- **Award type:** 5
- **Project period:** 2020-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128199

## Citation

> US National Institutes of Health, RePORTER application 10128199, A Patient-Specific hiPSC Model of Nilotinib-Induced Peripheral Artery Disease Pharmacogenomics (5F31HL151160-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10128199. Licensed CC0.

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