Wednesday, April 2, 2025
4/2/2025
Vascular-targeted Atheroprotective Gene therapies to Prevent Vein Graft Failure - 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 by addressing VG failure and significantly impacting patients' morbidity and mortality. Our research team, along with leading expert collaborators, has the diverse expertise required to successfully carry out this project.
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