Thrombosis causes morbidity and mortality in many pathological conditions. Prevention by anticoagulants and anti-platelet agents and therapeutic thrombolysis by fibrinolytic plasminogen activators, PA have limited efficacy and marred by bleeding and brain injury. Our team: i) proposed that coupling to carrier red blood cells (RBC) will improve pharmacokinetics of fibrinolytic PA, permitting their preventive utility;ii) demonstrated a proof of principle for effective and safe thromboprophylaxis attained by re-infusion of RBC/tPA conjugates in animals (Nature Biotech 2003);and, iii) designed safe loading of circulating RBC by anti-RBC/tPA conjugates in vivo. In order to translate this promising prototype into clinically applicable thromboprophylaxis with clinically acceptable utility, safety and specificity, we now designed a series of anti-RBC scFv/PA fusion pro-drugs activated by thrombin. To test this platform for delivery of anti-thrombotic agents loaded on RBC carriers, we shall characterize: i) activities, pharmacokinetics and thrombin regulation of the anti-RBC scFv/PA pro-drugs (Aim 1);ii) their efficacy in mouse models of venous and arterial thrombosis (Aim 2);and, iii) safety: potential harm to RBC, bleeding, systemic effects and adverse effects in the CNS (Aim 3). Implementation of this grant will provide a basis for translation into the clinical domain of this potentially revolutionizing novel approach for safe and effective thromboprophylaxis.

Public Health Relevance

we have designed a new strategy for prophylaxis of thrombosis based on coupling of fibrinolytic pro-drug recombinant fusion constructs that safely bind to carrier red blood cells (RBC). We shall characterize activities and pharmacokinetics regulation of the drugs, efficacy and safety in mouse models of thrombosis. Implementation of this translational grant will provide a solid basis for clinical development of this potentially revolutionizing novel approach for thromboprophylaxis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL090697-04
Application #
8110517
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Kindzelski, Andrei L
Project Start
2008-09-22
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$393,750
Indirect Cost
Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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