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Phosphorothioate oligonucleotides inhibit the intrinsic tenase complex
1University of Texas Health Science Center at San Antonio, Department of Medicine/Hematology, San Antonio, TX, USA. sheehan@uthscsa.edu
Blood
|August 26, 1998
Summary
ISIS 2302, an antisense oligonucleotide, prolongs clotting times by inhibiting intrinsic tenase activity at low concentrations. This phosphorothioate backbone property suggests a new target for anticoagulation therapies.
Area of Science:
- Pharmacology
- Hematology
- Molecular Biology
Background:
- Antisense oligonucleotides (ASOs) are emerging therapeutics.
- ISIS 2302 is an ASO targeting intercellular adhesion molecule-1 mRNA.
- ASOs can influence coagulation parameters.
Purpose of the Study:
- To investigate the anticoagulant effects of ISIS 2302.
- To elucidate the mechanism of action behind ISIS 2302's impact on clotting times.
Main Methods:
- In vitro coagulation assays using human plasma and purified enzyme systems.
- Prothrombin time, thrombin time, and activated partial thromboplastin time (PTT) assays.
- Chromogenic assays to assess enzyme activity.
Main Results:
- High ISIS 2302 concentrations prolonged prothrombin and thrombin times.
- Low ISIS 2302 concentrations selectively prolonged PTT by inhibiting intrinsic tenase.
- Inhibition of intrinsic tenase was sequence-independent but required the phosphorothioate backbone.
Conclusions:
- ISIS 2302 exhibits anticoagulant effects primarily through intrinsic tenase inhibition at therapeutic concentrations.
- Phosphorothioate backbone is critical for this anticoagulant activity.
- Intrinsic tenase is a potential novel target for anticoagulation therapy.