Hemostasis-Independent targeted treatment of thrombosis

Case Western Reserve University, Cleveland OH

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): Thrombotic disorders, including myocardial infraction (MI), stroke, and pulmonary embolism (PE), are the leading causes of death worldwide. Current antiplatelet, anticoagulant, and fibrinolytic agents are effective at reducing ischemic complications but are associated with significant bleeding that adversely impacts mortality. The rationale for our proposal is that targeted anti-thrombotic drug delivery will enhance efficacy and reduce bleeding. Recently, MRP-14 was identified as a direct regulator of thrombosis through its association with the platelet receptor CD36. Therefore, MRP-14 targeting has potential as a dual-therapeutic approach - namely, it can be used to directly block thrombosis by interrupting MRP-14 binding to CD36 as well as for nanoparticle-directed delivery of a thrombolytic agent. Importantly, unlike alternate targets such as fibrin, MRP-14 deficiency has no effect on multiple hemostatic parameters, such as tail bleeding time, thrombin generation, or platelet adhesion/spreading. This proposal uses a combinatorial approach to determine peptides that simultaneously bind to MRP-14 while blocking binding to CD36. We will use nature-inspired tobacco mosaic virus (TMV), a 300 by 18 nm rod-shaped plant virus-based nanoparticle we have shown to have enhanced thrombus homing due to shape-based effects. The central hypothesis is that MRP-14 targeting will allow for inhibition of thrombosis and precise delivery of drug-bearing nanoparticles, thereby reducing the effective dose necessary for thrombolysis and limiting bleeding. This hypothesis will be tested with a photochemical mouse thrombosis model with the following two aims: peptides specific for MRP- 14 that blocks its downstream effects will be identified (Aim 1), and the the most promising peptides will be utilized to target thrombosis and the therapeutic efficacy will be evaluated in vitro and in vivo (Aim 2). This approach is innovative, as it will be the first to develop an MRP-14 targeting peptide that is capable of simultaneously disrupting MRP-14:CD36 signaling in platelets and targeting a thrombolytic agent to thrombus. This project paves the way for clinical translation, utilizing already FDA-approved alteplase and improving its safety and efficacy through active delivery. Completion of these aims will result in a targeted carrier system that will address current clinical challenges b providing a more efficacious therapeutic approach for thrombosis with limited bleeding.