# Vascular-targeted Atheroprotective Gene therapies to Prevent Vein Graft Failure

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2024 · $775,234

## Abstract

Autologous vein grafts (VG) are the most commonly used conduits in revascularization procedures for coronary
artery disease (CAD) and peripheral arterial disease (PAD). However, VG failure rates remain high, reaching 30-
50% for lower extremity bypass and over 50% for coronary artery bypass grafts (CABG) within 5 and 10 years,
respectively. Intimal hyperplasia (IH) is the primary cause of VG failure, accounting for more than 70% of cases.
While medical therapies have shown some benefit in reducing CABG failure, they have not been effective in
lower extremity vein bypass grafts. The pathogenesis of IH involves determinants such as endothelial injury at
the time of harvest, exposure to turbulent arterial hemodynamics, and other pre-existing atherogenic risk factors.
To prevent VG failure, maintaining endothelial integrity, reducing vascular inflammation and smooth muscle cell
(SMC) proliferation, accelerating re-endothelialization, and promoting positive extracellular matrix remodeling,
are crucial. Building upon our previous research on the A20 gene, which has characterized the multiple
atheroprotective functions and therapeutic benefits in several small animal models of obstructive vascular
diseases, we propose using A20 as a single therapeutic agent that can remarkably target all pathogenic culprits
of IH. Our pilot studies in a large animal model of VG failure, that were funded through an exploratory R21
mechanism, set the basis for the current proposal. Since A20 is an intracytoplasmic protein, our laboratory has
been actively involved in gene therapy research to develop vascular-targeted A20 vectors. In this proposal, we
aim to generate advanced adeno-associated viruses (AAV) and emerging circular RNA (CircRNA) platforms for
safe and efficient delivery of A20 into VG via a short ex vivo perfusion prior to implantation. A combination of
both CircRNA and AAV for robust, immediate and sustained expression of A20 may well be required to address
the complex pathogenesis of IH effectively. The aims of this proposal are articulated around: 1. Optimizing and
validating the feasibility of this first-in-class in human saphenous vein tissue cultures, and 2. conducting efficacy
studies in two large animal models of VG failure with high bio-fidelity to human disease. Positive results in these
relevant animal models are a necessary prelude prior to pre-IND filing. Additionally, for the first time, we will
perform an in-tissue analysis of the VG transcriptome using spatial transcriptomics, enabling fine granular
mapping of transgene distribution and expression levels in different vessel layers, and capturing cell-specific
transcriptomic signatures that demonstrate A20's therapeutic impact and ensure its safe use. We are excited
about the potential groundbreaking results of these studies, which will bring us closer to clinical readiness for a
revolutionary vascular-targeted A20 gene therapy. This therapy holds great promise to fulfill an unmet clinical
need ...

## Key facts

- **NIH application ID:** 10865217
- **Project number:** 1R01HL173557-01
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Manoj Bhasin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $775,234
- **Award type:** 1
- **Project period:** 2024-05-25 → 2028-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10865217

## Citation

> US National Institutes of Health, RePORTER application 10865217, Vascular-targeted Atheroprotective Gene therapies to Prevent Vein Graft Failure (1R01HL173557-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10865217. Licensed CC0.

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