# Using human liver tissue equivalents to optimize AAV-mediated GT and better define age-related clinical risks

> **NIH HL R01** · WAKE FOREST UNIVERSITY HEALTH SCIENCES · 2026 · $383,674

## Abstract

PROJECT SUMMARY
Gene therapy (GT) clinical trials using AAV vectors are poised to fulfill the promise of a safe, affordable, lifelong
correction of bleeding disorders following a single treatment. Still, clinical trials using AAV vectors to treat
hemophilia A (HA) in adults have underscored the hurdles, such as the presence of pre-existing AAV antibodies,
and unexpected risk of hepatoxicity in these patients. Importantly, this toxicity was not seen in preclinical animal
studies, highlighting the dangers of extrapolating data from animal models to humans. Since the next step for
GT to treat severe HA will be implementation of this approach in children, it is crucial to predict, as accurately as
possible, unforeseen risks in this population. Currently, is unknown whether the unexpected immune/
inflammatory responses seen are due to the use of AAV as a delivery vehicle, or they are caused by the forced
expression of FVIII within hepatocytes, which are not the native site of FVIII production. However, since similar
toxicity has not been seen in AAV clinical trials for hemophilia B (hepatocytes are the natural site of FIX
production), it is rational to posit that ectopic FVIII expression likely plays a role. In addition, preclinical data have
also shown that, at the high doses used, AAV, long assumed to be largely episomal, may exhibit significant
levels of host genome integration that could potentially drive clonal expansion and hepatocellular carcinoma
(HCC), the risk of which increases as a result of hepatocyte proliferation. These are critical questions to safely
extend the use of these potentially curative treatments to the pediatric population, in whom the higher proliferation
and more primitive state of the liver may increase these risks. The overall goal of the present proposal is to
utilize a human liver tissue equivalent (hLTE) platform to answer these questions and to determine the impact
recipient age has on these variables. We will use hLTE to test the overa

## Key facts

- **NIH application ID:** 11294261
- **Project number:** 5R01HL166462-04
- **Recipient organization:** WAKE FOREST UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Graca Duarte Almeida-Porada; Christopher D Porada
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** HL
- **Fiscal year:** 2026
- **Award amount:** $383,674
- **Award type:** 5
- **Project period:** 2023-02-15T00:00:00 → 2027-01-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11294261

## Citation

> US National Institutes of Health, RePORTER application 11294261, Using human liver tissue equivalents to optimize AAV-mediated GT and better define age-related clinical risks (5R01HL166462-04). Retrieved via AI Analytics 2026-06-30 from https://api.ai-analytics.org/grant/nih/11294261. Licensed CC0.

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