# Oxidation Resistant ApoA1 Gene Delivery Stents

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2020 · $823,802

## Abstract

Summary: Oxidation Resistant apoA1 Gene Delivery Stents
Stent angioplasty has led to dramatic improvements in outcomes for coronary artery disease. Drug eluting stents
(DES) have sharply reduced the incidence of in-stent restenosis (ISR). Nevertheless, ISR remains a problem,
especially for high risk patients, such as those with diabetes. This proposal will investigate gene delivery stents
(GDS) to address these unmet needs. The therapeutic strategy for GDS in this project is based on prevention of
oxidation of apolipoprotein A1 (apoA1). The program will investigate an apo-A1 gene construct that has 4
tryptophans substituted with phenylalanine (4WF), that both resists oxidation and enables apoA1 functionality
for reverse cholesterol transport. A 4WF apo-A1 AAV2 gene GDS will be studied in a well characterized, severe
model of diabetic atherosclerotic disease by using hypercholesterolemic diabetic swine (HDS). The HDS model
requires 20 weeks to develop, prior to stent angioplasty, resulting in pigs with advanced atherosclerosis and
diabetes; thus a five year project period is requested for the proposed study design. The central hypothesis of
this proposal is that GDS with AAV2 encoding 4WF apoA1 will both inhibit the pathophysiology of ISR and
mitigate oxidative mechanisms involved with atherogenesis in HDS.
 Aim 1: To formulate and characterize AAV stent-delivery components utilizing Type 2 AAV (GFP,
wild type apoA1, and 4WF apoA1), and study GDS local delivery mechanisms in HDS coronary arteries.
 Subaim 1a. Construct vectors, and formulate AAV linker reagents. AAV2 with a CMV promoter encoding
either green fluorescent protein (GFP) or wild-type human apoA1 have already been constructed, scaled up and
used in our feasibility studies in healthy pigs; 4WF apo-A1 gene constructs are underway. The AAV linking
system to be used will treat the stent surfaces with polyallylamine-bisphosphonate that has conjugation sites to
attach Protein G with thiol reactions, followed by affinity binding of anti-AAV2 antibody for vector attachment.
 Subaim 1b. One week AAV2 apoA1 & 4WF studies will examine in vivo the following groups: Group 1 -
control, bare metal stents; group 2 - AAV2-GFP; group 3 - AAV2-apoA1 (wild type); group 4 - AAV2-4WF apoA1
(oxidation resistant). The endpoints will include apoA1 expression, inflammation, differences in both arterial wall
oxidized apoA1 and oxidized amino acid formation, and vector biodistribution.
 Aim 2: Perform a therapeutic study evaluating the efficacy of GDS. The study design will be: Group 1,
bare metal stent (controls) or Group 2, wild type AAV2-apoA1 and Group 3, AAV2-4WF apoA1, in HDS coronary
arteries. Endpoints will include anti-ISR efficacy, inhibition of apoA1 oxidation, re-endothelialization, and
mitigation of regional atherosclerotic pathophysiology.
 The expected results will validate the therapeutic use of GDS, and will also demonstrate the superiority of
the oxidant resistant 4WF apoA1 isoform in preventing...

## Key facts

- **NIH application ID:** 9988488
- **Project number:** 5R01HL137762-04
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Ilia Fishbein
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $823,802
- **Award type:** 5
- **Project period:** 2017-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988488

## Citation

> US National Institutes of Health, RePORTER application 9988488, Oxidation Resistant ApoA1 Gene Delivery Stents (5R01HL137762-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9988488. Licensed CC0.

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