Immune phenotype and function of natural killer and T cells in chronic hepatitis C patients who received a single dose of anti-MicroRNA-122, RG-101.

Abstract

MicroRNA-122 is an important host factor for the hepatitis C virus (HCV). Treatment with RG-101, an N-acetylgalactosamine-conjugated anti-microRNA-122 oligonucleotide, resulted in a significant viral load reduction in patients with chronic HCV infection. Here, we analyzed the effects of RG-101 therapy on antiviral immunity. Thirty-two chronic HCV patients infected with HCV genotypes 1, 3, and 4 received a single subcutaneous administration of RG-101 at 2 mg/kg (n = 14) or 4 mg/kg (n = 14) or received a placebo (n = 2/dosing group). Plasma and peripheral blood mononuclear cells were collected at multiple time points, and comprehensive immunological analyses were performed. Following RG-101 administration, HCV RNA declined in all patients (mean decline at week 2, 3.27 log10 IU/mL). At week 8 HCV RNA was undetectable in 15/28 patients. Plasma interferon-γ-induced protein 10 (IP-10) levels declined significantly upon dosing with RG-101. Furthermore, the frequency of natural killer (NK) cells increased, the proportion of NK cells expressing activating receptors normalized, and NK cell interferon-γ production decreased after RG-101 dosing. Functional HCV-specific interferon-γ T-cell responses did not significantly change in patients who had undetectable HCV RNA levels by week 8 post-RG-101 injection. No increase in the magnitude of HCV-specific T-cell responses was observed at later time points, including 3 patients who were HCV RNA-negative 76 weeks postdosing.

CONCLUSION:

Dosing with RG-101 is associated with a restoration of NK-cell proportions and a decrease of NK cells expressing activation receptors; however, the magnitude and functionality of ex vivo HCV-specific T-cell responses did not increase following RG-101 injection, suggesting that NK cells, but not HCV adaptive immunity, may contribute to HCV viral control following RG-101 therapy. (Hepatology 2017;66:57-68).

• Authors: Femke Stelma, Meike H van der Ree, Marjan J Sinnige, Anthony Brown, Leo Swadling, J Marleen L de Vree, Sophie B Willemse, Marc van der Valk, Paul Grint, Steven Neben, Paul Klenerman, Eleanor Barnes, Neeltje A Kootstra, Hendrik W Reesink
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 66 Issue 1 Pg. 57-68 (07 2017) ISSN: 1527-3350 [Electronic] United States
• PMID: 28295463 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2017 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.

Chemical References

• MicroRNAs

Topics

• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Administration Schedule
• Enzyme-Linked Immunospot Assay (methods)
• Female
• Flow Cytometry
• Follow-Up Studies
• Hepatitis C, Chronic (diagnosis, drug therapy)
• Humans
• Injections, Subcutaneous
• Killer Cells, Natural (drug effects, immunology)
• Male
• MicroRNAs (administration & dosage, antagonists & inhibitors)
• Middle Aged
• Molecular Targeted Therapy (methods)
• Netherlands
• Phenotype
• T-Lymphocytes (drug effects, immunology)
• Treatment Outcome