Antithrombotic effect of antisense factor xi oligonucleotide treatment in primates

Jeffrey R. Crosby, Ulla Marzec, Alexey S. Revenko, Chenguang Zhao, Dacao Gao, Anton Matafonov, David Gailani, A. Robert MacLeod, Erik I. Tucker, Andras Gruber, Stephen R. Hanson, Brett P. Monia

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

Objective-During coagulation, factor IX (FIX) is activated by 2 distinct mechanisms mediated by the active proteases of either FVIIa or FXIa. Both coagulation factors may contribute to thrombosis; FXI, however, plays only a limited role in the arrest of bleeding. Therefore, therapeutic targeting of FXI may produce an antithrombotic effect with relatively low hemostatic risk. Approach and Results-We have reported that reducing FXI levels with FXI antisense oligonucleotides produces antithrombotic activity in mice, and that administration of FXI antisense oligonucleotides to primates decreases circulating FXI levels and activity in a dose-dependent and time-dependent manner. Here, we evaluated the relationship between FXI plasma levels and thrombogenicity in an established baboon model of thrombosis and hemostasis. In previous studies with this model, antibody-induced inhibition of FXI produced potent antithrombotic effects. In the present article, antisense oligonucleotides-mediated reduction of FXI plasma levels by =50% resulted in a demonstrable and sustained antithrombotic effect without an increased risk of bleeding. Conclusions-These results indicate that reducing FXI levels using antisense oligonucleotides is a promising alternative to direct FXI inhibition, and that targeting FXI may be potentially safer than conventional antithrombotic therapies that can markedly impair primary hemostasis.

Original languageEnglish
Pages (from-to)1670-1678
Number of pages9
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume33
Issue number7
DOIs
Publication statusPublished - Jul 2013
Externally publishedYes

    Fingerprint

Keywords

  • Antisense oligonucleotide
  • Factor XI
  • Platelets
  • Thrombus formation
  • Vascular graft

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Crosby, J. R., Marzec, U., Revenko, A. S., Zhao, C., Gao, D., Matafonov, A., Gailani, D., MacLeod, A. R., Tucker, E. I., Gruber, A., Hanson, S. R., & Monia, B. P. (2013). Antithrombotic effect of antisense factor xi oligonucleotide treatment in primates. Arteriosclerosis, Thrombosis, and Vascular Biology, 33(7), 1670-1678. https://doi.org/10.1161/ATVBAHA.113.301282