Cardiovascular disease (CVD) remains the number one cause of death in the U.S. Left untreated, CVD can result in the occlusion of key arteries that can precipitate a major cardiac event. Clinicians routinely correct arterial blockages mechanically using a balloon expansion of the lesioned area and placement of a metallic stent to help keep the arteries open. However, the overstretch of the vessel that takes place during the intervention is damaging to the artery wall. This damage often precipitates a re-narrowing of the artery (restenosis) due to the proliferation of smooth muscle cells within the vascular wall. Drug-eluting stents (DES) were developed to inhibit smooth muscle cell proliferation, but have the disadvantage that while keeping the arteries open, they also prevent the relining of the vessel wall with a functional endothelial cell layer. This requires that patients undergo long-term treatment with dual anti-platelet therapies in order to prevent rare, but often fatal late-term clotting events at the site of the implant. The applicant has developed a new coating for the endovascular drug delivery of synergistic natural products that prevent the negative responses to angioplasty treatment that promote artery re-narrowing. However, unlike the drugs currently used for stent coatings, these compounds have been shown to actively accelerate endothelial wound healing. Moreover, our preliminary data utilizing a rat model of stenting and angioplasty showed that DES coated with resveratrol and quercetin (RQ-DES) dramatically reduced restenosis, while at the same time, accelerated re-endothelialization to complete the healing process. The significance of these new RQ-DES is that by promoting vascular healing (i.e., re-endothelialization), their use in vascular interventions could reduce the need for dual anti-platelet therapies, as well as provide for safer long term outcomes. In this phase I proposal, the applicant will utilize an FDA-accepted, clinically relevant rabbit model to test whether the RQ-DES promotes re-endothelialization compared to a commercial stent device. Complementary studies using other company funding will test whether the RQ- DES also reduces the extent of restenosis. These studies will set the stage for a larger phase II project aimed at fully characterizing the safety and efficacy of our coatings for further commercialization. Our commercialization efforts will be aimed at the use of an RQ coating for diverse applications, including coronary artery and peripheral artery diseases, as well as other applications in which neointimal hyperplasia contributes to clinical complications, such as in arteriovenous graft failure.

Public Health Relevance

Cardiovascular disease remains a leading cause of death in the United States. Clinicians routinely clear blocked arteries using angioplasty, a procedure in which a balloon is inflated in the blocked vessel so as to re- establish blood flow and prevent a major cardiac event. In 2003, the FDA approved the use of drug eluting stent (DES). DES is tubular devices meant to maintain blood flow through a blocked artery. The applicant is developing a novel technology to treat cardiovascular disease using cardio protective compounds that are found in red wine. The studies in this proposal will extend experiments using small animal models that suggest that DES releasing these compounds can promote vessel healing, while at the same time, preventing blood clotting and inflammation associated with DES implantation to address a critical, unmet medical need.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Small Business Technology Transfer (STTR) Grants - Phase I (R41)
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Special Emphasis Panel (ZRG1-CVRS-C (10))
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Fleg, Jerome
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Requisite Biomedical, LLC
United States
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