The goal of this proposal is for Matrexa to develop a protein product that will prevent intimal hyperplasia in human saphenous vein grafts (SVG) with the objective of reducing the exceedingly high failure rate of these surgical procedures. The strategy involves acute pre-treatment of saphenous veins at the time of surgery with proprietary agents, developed by Matrexa. The target for intervention is the large vascular matrix proteoglycan, versican, which is central to smooth muscle growth and hyperplasia, accumulation of atherogenic lipids, and macrophage ingress into developing lesions. We have successfully targeted versican and prevented these events in animal models of atherosclerosis through over expression of the small variant versican V3 (V3) and through over expression of versican antisense sequences. We have also discovered an additional and unexpected benefit of these approaches in that V3 promotes the synthesis and formation of elastic fibers and markedly improves the mechanical properties and stability of treated vessels. Once formed, the elastic fibers will maintain the structural integrity, anti-hyperplastic and anti-inflammatory nature of the vascular wall. We have further discovered, through deletion studies, that exon 3 of V3 contains this elastogenic activity. We recognize, however, that gene delivery and overexpression of V3 is therapeutically problematic for safety and other reasons and we therefore propose to develop and use rV3 protein and small peptides as therapeutic agents. In preliminary studies we have been successful in producing rV3 which possesses elastogenic activity.
The Aims of the project are 1) to prepare rV3 protein in enough quantity and purity to test its bioactivity in biochemical and in vitro cell-based assays and 2) to demonstrate the efficacy of rV3 to prevent intimal hyperplasia and promote elastogenesis in ex vivo cultures of human saphenous vein.
This project is designed to develop therapeutic compounds to treat cardiovascular disease, the number 1 killer of human beings in the western world. We have discovered a specific protein that blocks the development of atherosclerosis (fatty deposits in the artery walls that cause hardening of the arteries) in animal models of this disease and now want to use strategies to produce this protein and test its effectiveness as a therapeutic agent to treat artery bypass failure which is among the most common surgeries in the US, with over 500,000 performed per year. Success with this undertaking will have an enormous impact on health care in this country and worldwide.
|Merrilees, Mervyn J; Zuo, Ning; Evanko, Stephen P et al. (2016) G1 Domain of Versican Regulates Hyaluronan Organization and the Phenotype of Cultured Human Dermal Fibroblasts. J Histochem Cytochem 64:353-63|
|Kikuchi, Shinsuke; Kenagy, Richard D; Gao, Lu et al. (2016) Surgical marking pen dye inhibits saphenous vein cell proliferation and migration in saphenous vein graft tissue. J Vasc Surg 63:1044-50|
|Kang, Inkyung; Barth, Jeremy L; Sproul, Erin P et al. (2015) Expression of V3 Versican by Rat Arterial Smooth Muscle Cells Promotes Differentiated and Anti-inflammatory Phenotypes. J Biol Chem 290:21629-41|
|Wight, Thomas N; Kinsella, Michael G; Evanko, Stephen P et al. (2014) Versican and the regulation of cell phenotype in disease. Biochim Biophys Acta 1840:2441-51|
|Kang, Inkyung; Yoon, Dong Won; Braun, Kathleen R et al. (2014) Expression of versican V3 by arterial smooth muscle cells alters tumor growth factor ? (TGF?)-, epidermal growth factor (EGF)-, and nuclear factor ?B (NF?B)-dependent signaling pathways, creating a microenvironment that resists monocyte adhesion. J Biol Chem 289:15393-404|