Conte Lab Awarded Multiple Grants to Develop Drug-Device Preventing Restenosis in Cardiovascular Patients

Michael S. Conte, M.D., Professor and Chief of the Division of Vascular & Endovascular Surgery  and Director of the Conte Lab, has been awarded two grants to develop a prototype medical device that will deliver bioactive lipid mediators to prevent "restenosis", the recurrent narrowing of blood vessels following interventions such as angioplasty, stenting, and bypass surgery. The bioactive compounds are being developed in the Conte Lab. 

The first grant, a $200.000 Technology Development Award from the UC Center for Accelerated Innovation, is funded through a combination of grants and matching funds from a group comprised of National Heart, Lung and Blood Institute (UC CAI), UCSF School of Medicine, UCSF Department of Surgery, Division of Vascular and Endovascular Surgery, Boston Biomedical Innovation Center (B-BIC) and Brigham and Women's Hospital. 

The second grant, a $1.8M grant from the NHLBI Vascular Interventions/Innovations and Therapeutic Advances (VITA) Program, is for the development of a drug-device combination for prevention of restenosis. The VITA Program "is a new translational initiative of the National Heart, Lung, and Blood Institute (NHLBI) that enables and accelerates the development of promising diagnostic and therapeutic modalities for unmet and under-served medical needs".

The project manager for the grant is Evan C. Werlin, M.D., a resident research fellow in general surgery, who will conduct much of the reseach and work with the Desai Lab to optimize the device to deliver biologically active Resolvin to sites of vascular injury while minimizing the host's response to the device itself.

Dr. Conte sees great potential for the research to improve surgical outcomes in cardiovascular patients:  

With these awards, we are on the leading edge of translational research in vascular disease and hope to impact one of the most significant problems limiting long-term success in the treatment of cardiovascular and peripheral arterial disease: intimal hyperplasia. We are very fortunate to have this funding and look forward to moving our device closer to commercial production so that we can get it to the patients that need it most. 

Pro-Resolving micro-/nano-particles to improve vascular patency

• Funder: University of California Center For Accelerated Innovation (UC CAI) through NHLBI and others
• Award: Technology Development Award to facilitate nanoparticle formulations of resolvin for application to vein bypass grafts and angioplasty treatments
  
• Principal Investigator: Michael S. Conte, M.D., Co-I: Tejal Desai Ph.D.
• Amount: $130,032 direct / year 1 total $ 200,000
• Term:  8/1/16 – 7/31/18

The problem of vascular injury is pervasive throughout cardio-vascular surgical procedures, including vascular access, angioplasty, stenting and bypass surgery. Failure due to restenosis and vascular scarring is a continuing complication of most vascular interventions, creating an unmet medical need. Despite advances in drug‐eluting devices, most restenosis-blocking agents are cytotoxic compounds that retard rather than promote vessel wall healing. Recent studies suggest that specialized bioactive lipid mediators govern the resolution of inflammation,and have beneficial activity in healing vascular tissues. The goal of this VITA Program contract is use this biology to develop a prototype medical drug/device that effectively prevents restenosis and reduces vascular scarring.

VITA Stage B Project: Prevention of anastomotic intimal hyperplasia by a pro-resolving vascular device

• Funder: NHLBI Vascular Interventions/Innovations and Therapeutic Advances (VITA) Program
• VITA Stage B Project
• Project Objective: Innovative drug/device combination for prevention of restenosis
• 3 year, milestone based contract funding our development of devices to release omega-3 derived vasoprotective compounds ("resolvins") to promote surgical bypass patency, in a large animal model.
• Principal Investigator: Michael S. Conte, M.D.
• Project Manager and Lead Researcher: Evan C. Werlin, M.D.
• Award: Direct costs - $1.2 M ($1.8M with indirects)
• Term:  3 Years - Milestone-based - VITA 2 (2016-2018) 

Surgical bypass grafts are commonly employed for patients with advanced atherosclerotic occlusive disease in the coronary and peripheral circulations. Despite a high degree of technical success, the clinical durability of these procedures is limited by a scarring response that leads to vessel narrowing in 50% or more of cases within 3-5 years. Current drug therapies, such as anti-thrombotic and cholesterol-lowering agents, have only a modest effect on surgical bypass patency. The underlying pathophysiology involves inflammation and alterations in the phenotype of resident vascular cells (EC, VSMC) leading to cell proliferation, matrix production, and the development of a thickened neointima (intimal hyperplasia; IH) that reduces lumen patency.

This process can affect vascular grafts of all types, autogenous and prosthetic, and is frequently accentuated at the sites of vessel anastomoses. We have developed a bioengineering approach, based on the novel pharmacology of specialized lipid mediators (SPM) derived from polyunsaturated (omega-3) fatty acids that orchestrate the resolution phase of inflammation. In prior work we have demonstrated that SPM such as resolvin D1 (RvD1) exert beneficial effects on vascular cells and attenuate IH across several models of vascular injury.

In a Stage A NHLBI VITA-funded program, we developed and tested a thin-film biodegradable device that provides directional elution of RvD1 over several weeks in-vitro, and significantly inhibited IH in animal models of angioplasty and vein bypass grafting in-vivo. The device is applied as a perivascular “wrap” around a defined area of a blood vessel, such as a surgical bypass graft anastomosis, releasing RvD1 to the target tissue as it degrades.

We now propose to advance the preclinical development of this device to address the significant unmet need of preventing surgical bypass graft failure. In this Stage B VITA program we will standardize the manufacturing and packaging of a resolvin-eluting perivascular wrap, confirm desired biologic effects using a novel synthetic RvD1 analogue with enhanced bioavailability, and conduct large animal (ovine) studies to define safety and efficacy of this approach. At the conclusion of this three-year contract, we will have met multiple critical milestones toward a pre-IND stage of product development, and will outline the remaining regulatory and financial hurdles to achieve FDA approval for early stage human studies.