# Liquid biopsy technology towards individualized immunosuppression therapy

> **NIH NIH R21** · UNIVERSITY OF FLORIDA · 2024 · $192,625

## Abstract

PROJECT SUMMARY
 Transplantation of solid organs (liver, pancreas, spleen, adrenal glands, heart, lungs) can save the lives of
many patients with irreversible organ disease or injury. In the U.S., more than 40,000 transplants were performed
in 2021 alone. After a solid organ transplant, lifelong immunosuppressant therapy must be used to prevent and
treat organ rejection. The calcineurin inhibitor tacrolimus is a major therapeutic in such cases. Due to the risk of
organ rejection, infection, and drug toxicity, therapeutic drug monitoring is advised to ensure pharmacokinetic
(PK) targets. Typically, the need for precise dosing has been linked to genetic differences, particularly those
affecting drug PK. Despite the important role of pharmacogenomics in precision dosing, large expression
variability occurs within each genotype, which can be captured by expression data. Moreover, no known genetic
signatures define the wide expression variations for certain key enzymes, such as CYP3A4. Hence, assessing
variability in expression of gut and hepatic CYP3A4 is a promising alternative to inform drug development and
precision medicine. This promising approach may capture transcriptional regulation effects, such as the
downregulation of CYP3A4 by proinflammatory cytokines.
 Recent exploratory studies showed the application of plasma-derived extracellular vesicles (EV) and omics
technologies deployed as a liquid biopsy to assess the expression of drug-metabolizing enzymes and
transporters. Hence, EV are gaining traction as new phenotyping biomarkers. Various EVs are shed into the
blood and contain cargo representing their tissue of origin. Building upon earlier findings, we will answer the
following research question: Can we use liver-derived EV as in vivo CYP3A4/5 expression biomarkers to inform
tacrolimus dosing in liver transplant patients? A prospective clinical study will be conducted in patients
undergoing liver transplants to explore whether liver and gut-derived EV expression data can be used to predict
the variability in tacrolimus pharmacokinetics and ultimately to propose an optimal dosing regimen. In summary,
we will integrate PK, transcriptomic data, and modeling and simulation to establish an innovative strategy to
individualize tacrolimus dosing. The use of expression data to support precision dosing can potentially overcome
the exclusion of under-represented population subgroups (e.g. rare genetic variants of CYP3A4/5 and P-
glycoprotein (P-gp). Thus, this proposal will promote diversity in immunosuppression therapy by enhancing the
number of subjects responding to tacrolimus efficacy and reducing the risk of adverse reactions. Our research
will develop an integrated package of highly predictive mathematical models and dosing optimization strategies
for tacrolimus. By tracking different sources of variability in tacrolimus pharmacokinetics, we will inform precision
public health interventions in solid organ transplant patients. Importantly, ou...

## Key facts

- **NIH application ID:** 10988708
- **Project number:** 1R21DK138414-01A1
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Natalia Valadares De Moraes
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $192,625
- **Award type:** 1
- **Project period:** 2024-08-29 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10988708

## Citation

> US National Institutes of Health, RePORTER application 10988708, Liquid biopsy technology towards individualized immunosuppression therapy (1R21DK138414-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10988708. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*