# Human Hepatocyte and Discovery Core

> **NIH NIH P01** · INDIANA UNIVERSITY INDIANAPOLIS · 2022 · $405,486

## Abstract

PROJECT SUMMARY/ABSTRACT
Gene therapy for hemophilia A holds promise to accomplish a lasting cure. Adeno-associated viral (AAV) gene
transfer of clotting factor FVIII to the livers of males can achieve therapeutic correction but this is not sustained.
The reasons for hepatotoxicity and the decline in FVIII expression in clinical trials are unclear. The AAV therapies
currently under investigation target hepatocytes in the liver. There is, however, a limited understanding of the
interactions between the vector and hepatocytes as well as effect of FVIII expression and immune responses.
Core B will provide primary human hepatocyte models to address these basic and mechanistic questions related
to the biology of AAV and FVIII. The central hypothesis of this proposal is that multiple interconnected features
of AAV and FVIII biology limit durability of therapeutic expression and pose serious safety concerns. The
objectives of Core B, the Human Hepatocyte and Discovery Core, is to provide three primary human hepatocytes
models to study AAV vector and FVIII biology. The first model is primary hepatocyte cultures that retain stable
hepatocyte functions in 2-dimensional format. These will be used for in vitro studies. The second model is
chimeric mice whose livers are highly repopulated with primary human hepatocytes. These will be used for in
vivo AAV studies. And the third model is mice doubly engrafted with hematopoietic stem cells and livers for in
vivo studies of human immune cells in the liver. Core B will provide these services to investigators to address
major unanswered questions in FVIII biology, gene therapy for hemophilia, liver-directed gene transfer, and
molecular and immunobiology of AAV vectors.

## Key facts

- **NIH application ID:** 10333187
- **Project number:** 1P01HL160472-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Ype Peter De Jong
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $405,486
- **Award type:** 1
- **Project period:** 2022-02-05 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10333187

## Citation

> US National Institutes of Health, RePORTER application 10333187, Human Hepatocyte and Discovery Core (1P01HL160472-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10333187. Licensed CC0.

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