Intracerebroventricular Administration of a 2 '-O-Methyl Phosphorothioate Antisense Oligonucleotide Results in Activation of the Innate Immune System in Mouse Brain

Lodewijk J. A. Toonen, Joao Casaca-Carreira, Maria Pellise-Tintore, Hailiang Mei, Yasin Temel, Ali Jahanshahi, Willeke M. C. van Roon-Mom*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

11 Citations (Web of Science)

Abstract

Antisense oligonucleotides (AONs) are versatile molecules that can be used to modulate gene expression by binding to RNA. The therapeutic potential of AONs appears particularly high in the central nervous system, due to excellent distribution and uptake in brain cells, as well as good tolerability in clinical trials thus far. Nonetheless, immune stimulation in response to AON treatment in the brain remains a concern. For this reason we performed RNA sequencing analysis of brain tissue from mice treated intracerebroventricularly with phosphorothioate, 2-O-methyl modified AONs. A significant upregulation of immune system associated genes was observed in brains of AON treated mice, with the striatum showing largest transcriptional changes. Strongest upregulation was seen for the antiviral enzyme 2-5-oligoadenylate synthase-like protein 2 (Oasl2) and Bone marrow stromal antigen 2 (Bst2). Histological analysis confirmed activation of microglia and astrocytes in striatum. The upregulation of immune system associated genes was detectable for at least 2 months after the last AON administration, consistent with a continuous immune response to the AON.
Original languageEnglish
Pages (from-to)63-73
Number of pages11
JournalNucleic Acid Therapeutics
Volume28
Issue number2
DOIs
Publication statusPublished - 1 Apr 2018

Keywords

  • immune stimulation
  • antisense oligonucleotide
  • 2 '-O-methyl
  • mouse brain
  • CENTRAL-NERVOUS-SYSTEM
  • DIFFERENTIAL EXPRESSION ANALYSIS
  • TOLL-LIKE RECEPTORS
  • 2',5'-OLIGOADENYLATE SYNTHETASE
  • COMPLEMENT ACTIVATION
  • HUNTINGTONS-DISEASE
  • NONHUMAN-PRIMATES
  • STRANDED RNA
  • IN-VIVO
  • OLIGODEOXYNUCLEOTIDES

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