Using a novel in vitro selection/amplification technique termed """"""""aptamer technology"""""""", we have identified a new class of thrombin inhibitors based on single-stranded DNA (ssDNA) oligonucleotides (Bock et al. Nature 355, 564-6, 1992). One oligonucleotide GGTTGGTGTGGTTGG (thrombin aptamer), showed potent anticoagulant activity in vitro and in vivo. Pharmacological studies in cynomolgus monkeys showed the thrombin aptamer to have a rapid onset of action and short half-life in vivo. The short in vivo half-life permitted regional anticoagulation of an extracorporaal hemofiltration circuit in sheep, and successful anticoagulation in a canine cardiopulmonary bypass model.
The specific aims of this project are: 1) To assess the efficacy of the thrombin aptamer as an anticoagulant in canine and primate models of cardiopulmonary bypass which will obviate the use of protamine sulfate and may reduce the use of blood products; 2) To test the efficacy of the thrombin aptamer as a regional anticoagulant in non-human primate hemodialysis which may minimize the bleeding risks associated with systemic anticoagulation; 3) To develop a cost efficient, large scale manufacturing process for the thrombin aptamer. Our ultimate goal is to develop this novel ssDNA based thrombin aptamer as an anticoagulant superior to heparin for use in cardiopulmonary bypass and hemodialysis in Phase III clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
2R44HL048431-02
Application #
3508889
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1993-09-30
Project End
1995-08-31
Budget Start
1993-09-30
Budget End
1994-08-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Tcw Pharmaceutical Corporation
Department
Type
DUNS #
City
Cupertino
State
CA
Country
United States
Zip Code
95014