# Genetic Engineering of Vein Bypass Grafts in Vascular and Cardiovascular Surgery

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $799,279

## Abstract

PROJECT SUMMARY/ABSTRACT
Autologous vein grafts are the most common and most effective bypass grafts when used in the heart to treat
coronary artery disease or in the lower extremity to prevent amputations. Nonetheless the delayed failure rate
of vein grafts is about 30%, almost all due to intimal hyperpalsia (IH). IH, in turn, is an integral part of the
response to implantation injury when the vein is moved from the low pressure, vasa vasorum dependent
physiology, to the high pressure, luminal dependent physiology of the arterial system. Our goal is to minimize
this implantation injury, and thereby diminish the maladaptive, pathologic remodeling associated with IH. Our
experimental design has always been guided by practical considerations whereby the therapeutic intervention
could be conducted within the clinical constraints of the operating room. Our strategy has been to first
determine the time dependent gene expression response (transcriptome), 1 day to 30 days after implantation,
followed by identifying the most important ‘Hub” genes that drive the pathologic remodeling. Our therapeutic
approach is to silence these pathogenic hub genes in the vascular wall. Therefore, we knocked down and
tested two of our most promising targets, Thrombospondin-2 (TSP-2) and Myristoylated alanine-rich C-kinase
substrate (MARCKS) in two different reproducible large animal models to document molecular and histologic
outcomes. Going forward we are going to supplement our therapeutic regimen by overexpressing the
atheroprotective, anti-inflammatory gene, TNF-alpha induced protein-3 (TNFAIP3 or A20), using clinically
applicable vasculotropic gene therapy vectors. A multimodal and bidirectional (knockdown of atherogenic and
overexpression of atheroprotective genes) therapeutic regimen may well be required to address the complex
pathogenesis of IH. Using, for the first time, the state-of-the-art integrated single cell (Sc), coupled with bulk
RNA-sequencing we will map the transcriptomic granularity of the VG heterogeneous response to implantation
injury and to therapy. This could determine more precisely the role of vascular and non-vascular, yet influential,
cellular subsets such as immune cells, myofibroblasts etc. in the pathogenesis of VG implantation injury. Our
preliminary results in a canine vein graft model with high biofidelity to human disease uncovers pertinent novel
information, highlighting a so far underestimated contribution of pathogenic T helper 1 cells (Th1) to VG
remodeling. These new experiments will bring us to preclinical readiness in a strategy designed to use the
most advanced delivery systems and molecular technologies to reduce implantation injury to vein grafts and
diminish IH in other vascular diseases. Our research team is structured to take advantage of the MPI format to
coalesce the broad expertise required to bring this project to fruition and maintain an enduring focus on the IH
problem.

## Key facts

- **NIH application ID:** 9841961
- **Project number:** 5R01HL086741-11
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** Manoj Bhasin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $799,279
- **Award type:** 5
- **Project period:** 2007-02-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841961

## Citation

> US National Institutes of Health, RePORTER application 9841961, Genetic Engineering of Vein Bypass Grafts in Vascular and Cardiovascular Surgery (5R01HL086741-11). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9841961. Licensed CC0.

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