Currently, more than 60 % of end-stage renal diseases patients who require chronic hemodialysis are accessed through a native arteriovenous fistula (AVF) or synthetic graft (AVG). Unfortunately, primary failure rates were as high as 60 % at 6 months after AVF creation and 77% at 1 year after AVG construction. Surgical trauma, repeated needle punctures, mechanical shear stress, the foreign graft material and uremia can elicit a strong thrombotic response that lays down a mural fibrin- and platelet-rich substrate on which excessive cell migration, proliferation and matrix deposition occur, leading to neointimal hyperplasia (NH) in the peri-anastomotic regions of AVFs and AVGs. Limiting the early event of mural thrombosis may thus effectively reduce NH, which is the primary cause of stenosis and subsequent dialysis access failure. Currently available antiplatelet and anticoagulant drugs, however, have inadequate efficacies in preventing NH at clinically safe doses. EVAS Therapeutics has developed two thrombogenic site-targeted fusion Proteins (ANV-6L15 and TAP-ANV), which can specifically dock onto the membrane surfaces of thrombogenic cells and passivate the membrane-associated enzyme/cofactor complexes that initiate and propagate the clotting cascade. Due to their high-affinity thrombogenic site-targeting properties and relatively short circulating half-lives, the fusion proteins can exert long-lasting antithrombotic effect without systemic anticoagulation. This may eliminate the need for long-term antithrombotic therapy and inhibit mural thrombosis more effectively with reduced risks of bleeding. The main objective of this proposal is to develop these promising drug candidates for prevention of NH and improving the function and survival of AVGs. If successful, this strategy can be applied to AVFs.
The specific aims of the phase II proposal are:
Specific aim 1 : Establish pilot-scale processes for production of ANV-6L15 and TAP-ANV. A bench process developed in phase I will be adapted for pilot-scale production of the recombinant proteins.
Specific aim 2 : Examine therapeutic efficacies of TAP-ANV and ANV-6L15 in porcine hemodialysis vascular access models. Both NH formation and lumen patency will be examined using a porcine arteriovenous polytetrafluoroethylene (PTFE) graft (AVG) model. Currently there are no effective therapies to improve hemodialysis arteriovenous access longevity. Through this study we may provide a novel and simple therapeutic intervention to improve longevity of hemodialysis PTFE AVGs and AVFs. Results from this study will also provide critical data for IND filing and further clinical development.
Performance of hemodialysis procedure requires a functional vascular access which often fails within one year. This project will examine the therapeutic efficacy of two novel antithrombotic drug candidates in preventing hemodialysis arteriovenous graft failure.
|Terry, Christi M; Zhuplatov, Ilya; He, Yuxia et al. (2015) Assessment of Novel Anti-thrombotic Fusion Proteins for Inhibition of Stenosis in a Porcine Model of Arteriovenous Graft. PLoS One 10:e0137381|
|Yeh, C-H; Chen, T-P; Wang, Y-C et al. (2013) Potent cardioprotection from ischemia-reperfusion injury by a two-domain fusion protein comprising annexin V and Kunitz protease inhibitor. J Thromb Haemost 11:1454-63|