Research Project
9347119
The long-term efficacy of vein graft transplantation, the most effective surgical treatment for occlusive vascular disease, is limited by eventual vein graft occlusion. A major cause of vein graft failure is neointimal (NI) hyperplasia, characterized by abnormal proliferation and accumulation of vascular smooth muscle cells (SMCs). However, targeting vascular SMCs showed little efficacy in preventing vein graft failure, indicating the need for new approaches. Our recent findings indicate that the activation of resident vascular stem cells (VSCs) in vein grafts soon after transplantation plays an essential role in neointimal hyperplasia. We have developed the first selective small-molecule inhibitors of cyclin dependent kinase (CDK)8, a transcription-regulating kinase, which does not mediate cell division but regulates certain biological programs including stem cell differentiation. We have found that CDK8 inhibitors selectively suppress VSC proliferation and differentiation. When administered locally or systemically, these compounds inhibited NI hyperplasia of transplanted veins in a mouse model, with 3-day local drug application sufficient to prevent graft occlusion 100 days after transplantation. These results suggest a therapeutic potential of CDK8 inhibitors as VSC-modulating agents for the prevention of vein graft failure. The lead systemic CDK8 inhibitor, Senexin B shows no limiting toxicities at therapeutically effective doses and is being developed as a cancer drug candidate. We now propose to investigate the potential utility of this drug in vascular surgery. This Phase I study will establish the efficacy of Senexin B for the treatment of vein graft failure in a mouse model and the underlying mechanisms of this effect. Aim 1 is to identify the time frame of Senexin B administration required to prevent neointimal hyperplasia in vein grafts and to establish the long-term efficacy of short-term treatment with Senexin B in preventing vein graft failure. Here, Senexin B will be first delivered to mice at a single high dose daily for a different number of days, and its effect on neointima formation will be determined 28 days after transplantation. In the next study, the drug will be delivered to mice at two different doses, over the time frame established in the first study, and the long-term treatment efficacy and dose dependence will be evaluated 100 days after transplantation. Aim 2 is to characterize the pharmacodynamic effects of Senexin B on CDK8 activity, cellular dynamics and function of transplanted vein grafts. This aim will use tissues collected shortly (3 and 7 days) after transplantation. The effects of Senexin B on CDK8 activity, hemodynamic functional surrogates of vein grafts, cellular dynamics of vascular VSC, vascular SMC, endothelial cells, leukocytes and T cells, and expression of SMC markers and growth factors will be determined by immunohistochemistry, immunoblotting and RNA analysis. This work will pave the way for the Phase II study, which will test the efficacy of CDK8 inhibitors in large mammals, with additional pharmacokinetics and toxicology analysis, in preparation for clinical testing of this novel approach to preventing vasculopathies associated with NI hyperplasia.
