Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Interferon-α receptor antisense oligonucleotides reduce neuroinflammation and neuropathology in a mouse model of cerebral interferonopathy
Barney Viengkhou, … , Fredrik Kamme, Markus J. Hofer
Barney Viengkhou, … , Fredrik Kamme, Markus J. Hofer
Published February 15, 2024
Citation Information: J Clin Invest. 2024;134(4):e169562. https://doi.org/10.1172/JCI169562.
View: Text | PDF
Research Article Inflammation Neuroscience Article has an altmetric score of 42

Interferon-α receptor antisense oligonucleotides reduce neuroinflammation and neuropathology in a mouse model of cerebral interferonopathy

  • Text
  • PDF
Abstract

Chronic and elevated levels of the antiviral cytokine IFN-α in the brain are neurotoxic. This is best observed in patients with genetic cerebral interferonopathies such as Aicardi-Goutières syndrome. Cerebral interferonopathies typically manifest in early childhood and lead to debilitating disease and premature death. There is no cure for these diseases with existing treatments largely aimed at managing symptoms. Thus, an effective therapeutic strategy is urgently needed. Here, we investigated the effect of antisense oligonucleotides targeting the murine IFN-α receptor (Ifnar1 ASOs) in a transgenic mouse model of cerebral interferonopathy. Intracerebroventricular injection of Ifnar1 ASOs into transgenic mice with brain-targeted chronic IFN-α production resulted in a blunted cerebral interferon signature, reduced neuroinflammation, restoration of blood-brain barrier integrity, absence of tissue destruction, and lessened neuronal damage. Remarkably, Ifnar1 ASO treatment was also effective when given after the onset of neuropathological changes, as it reversed such disease-related features. We conclude that ASOs targeting the IFN-α receptor halt and reverse progression of IFN-α–mediated neuroinflammation and neurotoxicity, opening what we believe to be a new and promising approach for the treatment of patients with cerebral interferonopathies.

Authors

Barney Viengkhou, Christine Hong, Curt Mazur, Sagar Damle, Nicholas B. Gallo, Terry C. Fang, Kate Henry, Iain L. Campbell, Fredrik Kamme, Markus J. Hofer

×

Figure 3

Delayed Ifnar1 ASO dosing reduces Ifnar1 transcript and NF-H disease biomarker levels in GIFN mice with established neuropathology.

Options: View larger image (or click on image) Download as PowerPoint
Delayed Ifnar1 ASO dosing reduces Ifnar1 transcript and NF-H disease bio...
(A) Schematic of the experiment. Tail blood was taken 1 week prior to the second dose and/or 1 week prior to euthanasia. (B) Real-time qPCR of relative Ifnar1 expression in cortex and spinal cord of mice (n = 6–8 per genotype per treatment). Each point is a mouse and mean and SEM shown. 2-way ANOVA with Tukey’s post test. (C) Relative level of serum NF-H in treated WT and GIFN mice (n = 5–6 mice per genotype per treatment). Each point is a mouse and mean and SEM are shown. **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA with Tukey’s post test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Picked up by 5 news outlets
Blogged by 1
Posted by 5 X users
On 1 Facebook pages
15 readers on Mendeley
See more details