# Modeling Drug Induced Liver Injury with Patient-Derived Liver Organoids and Microfluidic Chips

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $508,057

## Abstract

ABSTRACT
Drug-induced liver injury (DILI) is an infrequent but important cause of both acute and chronic liver disease.
The symptoms of DILI can be vague and non-specific, and may not appear until weeks or months after drug
administration. While most cases of DILI are mild and resolve by stopping the offending medication, in some
cases it can lead to liver failure requiring transplantation or death. Additionally, there are no drugs or therapies
that can reverse the liver damage caused by DILI. An estimated 22% of clinical trial failures and 32% of market
withdrawals of novel molecular entities are due to unanticipated hepatotoxicity. The combination of iPSC-
derived human liver organoids (HLOs) from DILI patients with organ-on-chip technology has the potential to
revolutionize DILI risk prediction and may ultimately lead to the development of safer and more effective
medications. We have established a biobank from 15 well-characterized U-M patients enrolled in DILIN along
with methods to engineer liver tissue that can recapitulate their specific disease phenotype to enable
mechanistic inquiry and establish improved animal-free methods for predicting DILI. We propose to fully
develop a next-generation DILI risk prediction platform to improve predictive accuracy and improve our
understanding of the etiopathogenesis and biomarkers of DILI due to specific drugs or HDS products. We
hypothesize that HLOs from diverse DILI patients will provide a novel and scalable platform for risk prediction
and mechanistic inquiry. We will test this hypothesis with three Specific Aims: (1) expand DILI patient biobank
through more patient enrollment to enhance the ethnic and gender diversity and the number of culprit drugs to
characterize more mechanisms of DILI, (2) increase the model complexity by incorporating additional liver cell
types including same-patient immune cells, cholangiocytes, and an endothelial barrier that will be more
physiologically active to enable high accuracy in retrospective prediction of the culprit drug, (3) perform state-
of-the-art single-cell mechanistic studies involving selected drugs including amoxicillin-clavulanate and link
genotype and transcriptional profiles to cellular phenotypes following drug exposure. The top identified targets
will be validated by CRISPR genome editing, functional assessment, and differential hepatotoxicity for DILI
drugs.

## Key facts

- **NIH application ID:** 10772733
- **Project number:** 1R01GM152417-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** ROBERT J FONTANA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $508,057
- **Award type:** 1
- **Project period:** 2024-02-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10772733

## Citation

> US National Institutes of Health, RePORTER application 10772733, Modeling Drug Induced Liver Injury with Patient-Derived Liver Organoids and Microfluidic Chips (1R01GM152417-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10772733. Licensed CC0.

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