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Antisense oligonucleotides and nucleic acids generate hypersensitive platelets.

Alexander Zaslavsky1, Mackenzie Adams1, Xiu Cao1

  • 1Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA.

Thrombosis Research
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Summary
This summary is machine-generated.

Nucleic acids, not just their backbone, can make platelets hypersensitive, potentially causing thrombosis. This finding suggests ex vivo platelet testing before antisense oligonucleotide therapy in patients.

Keywords:
Antisense oligonucleotidesPlateletsProstate CancerToll-like receptors

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Area of Science:

  • Biochemistry
  • Immunology
  • Pharmacology

Background:

  • Antisense oligonucleotides (ASOs) show therapeutic promise but cause adverse effects like thrombocytopenia.
  • These effects were previously attributed to the phosphorothioate (PS) backbone of ASOs.
  • The role of the nucleic acid (NA) component itself in ASO-related side effects was unclear.

Purpose of the Study:

  • To investigate the impact of the NA portion of ASO-type drugs on platelet function.
  • To determine if NAs contribute to thrombosis or thrombocytopenia.
  • To explore the mechanisms underlying NA-induced platelet activation.

Main Methods:

  • Platelets were isolated from healthy donors and prostate cancer patients.
  • Assessed effects of ASOs, oligonucleotides, genomic DNA (gDNA), and microRNA (miRNA) on platelet activation and aggregation.
  • Utilized a mouse model of lung thrombosis to evaluate in vivo effects of PS-modified oligonucleotides.

Main Results:

  • Exposure to gDNA, miRNA, and oligonucleotides (>16-mer, >8 µM) induced hypersensitive platelets.
  • Hypersensitive platelets showed increased sensitivity to thrombin and elevated p-Selectin expression (TLR-7 dependent).
  • A p-Selectin inhibitor reduced oligonucleotide-associated pulmonary microthrombosis in vivo.

Conclusions:

  • Platelet hypersensitivity and activation by NAs occur independently of PS modification.
  • Toll-like receptor (TLR)-7 subfamily receptors mediate these NA-induced platelet effects.
  • Ex vivo platelet testing is recommended before initiating ASO therapy in cancer patients.