# Atheroprotective Gene Therapy

> **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2021 · $720,435

## Abstract

PROJECT SUMMARY
Atherosclerosis is a disease of the blood vessel wall that causes heart attacks and strokes. Despite major
advances in medical and surgical management, atherosclerosis still causes significant morbidity and mortality.
For example, drug therapy that dramatically lowers LDL-cholesterol (to ~30 mg/dL) only marginally decreases
adverse cardiovascular events and mortality. New approaches, beyond LDL lowering, are needed. The broad,
long-term objective of this project is to develop a therapy that prevents and reverses atherosclerosis via
interventions targeted at the blood vessel wall. This novel therapy involves the introduction and expression of
disease-preventing genes in the cells that line blood vessel walls and is accordingly termed “atheroprotective
gene therapy.” Blood vessels treated with this gene therapy would not develop atherosclerosis because they
are genetically modified to resist the underlying biological processes that cause atherosclerosis: accumulation
of cholesterol and inflammatory cells and activation of vascular cell inflammatory pathways. This project is
focused on gene therapy that prevents cholesterol accumulation (and associated inflammation) in blood vessel
walls. Vessel wall-targeted gene therapy is particularly well suited for prevention of atherosclerosis in veins
used for coronary artery bypass grafts. Vein-graft atherosclerosis progresses rapidly, leads to graft narrowing
and occlusion, and is inadequately treated. Our approach could eventually eliminate vein-graft atherosclerosis.
There are 3 specific aims, all of which are carried out in rabbits. The aims are focused on developing clinically
useful atheroprotective gene therapy, delivered by a promising gene-transfer vector, “helper-dependent
adenovirus” (HDAd). HDAd is an attractive vector for human gene therapy because it expresses therapeutic
genes stably for years in animals (including nonhuman primates) and is relatively non-inflammatory. The 3
specific aims exploit the promise of HDAd and take the next critical steps towards developing gene therapy
that prevents and reverses atherosclerosis: Aim 1 will test whether HDAd-mediated expression of
apolipoprotein A-I (apoA-I) or ATP-binding cassette subfamily A, member 1 (ABCA1) can prevent
atherosclerosis in grafted rabbit veins. Aim 2 will develop novel expression cassettes that achieve high-level,
stable, cell-specific transgene expression in endothelium in vivo. Aim 3 will identify the mechanisms through
which atheroprotective gene therapy that produces apoA-I from endothelial cells prevents atherosclerosis.
Accomplishment of the 3 aims will bring clinical vascular gene therapy closer to implementation by testing 2
promising therapeutic genes in a large animal model (Aim 1). Accomplishment of the aims may also yield novel
vector platforms that are useful for expressing transgenes at high levels in endothelial cells and may also
provide insights into mechanisms of endothelial cell gene transcription...

## Key facts

- **NIH application ID:** 10078619
- **Project number:** 5R01HL114541-07
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** David A Dichek
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $720,435
- **Award type:** 5
- **Project period:** 2013-06-10 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10078619

## Citation

> US National Institutes of Health, RePORTER application 10078619, Atheroprotective Gene Therapy (5R01HL114541-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10078619. Licensed CC0.

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