# Targeting AAV vectors to cell types involved in alcohol-induced liver injury

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $316,666

## Abstract

Project Summary/Abstract
Alcoholic liver disease is a major clinical challenge because it is associated with severe complications like liver
cirrhosis and alcoholic hepatitis, which carry a high mortality. Our understanding of the mechanisms underlying
alcoholic liver disease is still evolving; however, previous research has identified cells involved in the liver's
response to alcohol-induced injury, including myofibroblasts, macrophages and oval cells (called ductular
reaction in humans). Because of their unique and important functions, each of these cell types is a promising
therapeutic target. Macrophages initiate and promote liver inflammation and activate hepatic stellate cells,
which leads to the formation of collagen-secreting myofibroblasts and liver fibrosis and cirrhosis. Other types of
macrophages resolve fibrosis and oval cells may produce new hepatocytes, although oval cell accumulation
does not appear to prevent liver failure in patients with alcoholic hepatitis. Efficient gene delivery to these cell
types would facilitate inhibiting or activating these functions, which would have many applications in research
and therapy of alcoholic liver disease. To achieve this overall goal, we aim to target nonintegrating nontoxic
adenoassociated viral (AAV) vectors to (1) myofibroblasts, (2) macrophage subsets, i.e., Kupffer cells and pro-
inflammatory and anti-inflammatory infiltrating macrophages, and (3) oval cells in vivo. For this, we formed a
collaboration that combines our expertise in AAV vector engineering and the cellular and molecular biology of
liver injury and regeneration. To facilitate specific experimentation and support clinical translation, we will not
only target AAV vectors to each of these cell types but also detarget them from every other organ and cell type
in the body using a workflow that combines state-of-the-art AAV capsid evolution technology, faithful mouse
models of alcoholic liver disease, next-generation sequencing-based analysis of vector biodistribution and on-
target and off-target regulation of vector gene expression. To demonstrate the efficacy of the new synthetic
AAV capsids, we will use them to determine which of the targeted cell types is most susceptible to in vivo
reprogramming into hepatocytes. We hypothesize that oval cells can be most efficiently induced to become
hepatocytes because they derive from closely related cholangiocytes or hepatocytes themselves. Therefore, in
addition to providing efficient and precise tools for studies of alcohol-induced liver injury, the proposed project
may establish opportunities for new therapies for liver failure and other life-threatening complications of
alcoholic liver disease.

## Key facts

- **NIH application ID:** 9938307
- **Project number:** 5R01AA026578-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Holger Willenbring
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $316,666
- **Award type:** 5
- **Project period:** 2018-09-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938307

## Citation

> US National Institutes of Health, RePORTER application 9938307, Targeting AAV vectors to cell types involved in alcohol-induced liver injury (5R01AA026578-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9938307. Licensed CC0.

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