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 (miR-122) is an important host factor for the hepatitis C virus. Treatment with RG-101, a GalNAc conjugated anti-miR-122 oligonucleotide, resulted in a significant viral load reduction in patients with chronic hepatitis C (CHC) infection. Here, we analyzed the effects of RG-101 therapy on antiviral immunity. 32 CHC patients HCV genotype 1, 3 and 4 received a single subcutaneous administration with RG-101 at 2 mg/kg (n=14), 4 mg/kg (n=14) or placebo (n=2 per dosing group). Plasma and PBMCs 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 IP-10 levels declined significantly upon dosing with RG-101. Furthermore, the frequency of NK cells increased, the proportion of NK cells expressing activating receptors normalized and NK cell IFN-γ production decreased after RG-101 dosing. By week 8 post RG-101 injection, functional HCV-specific IFN-γ-T cell responses declined significantly in patients who had undetectable HCV RNA. 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 post dosing. Conclusions 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. Our data suggests that NK cells, but not HCV adaptive immunity may contribute to HCV viral control following RG-101 therapy.

Hepatitis C virus direct‐acting antivirals therapy impacts on extracellular vesicles microRNAs content and on their immunomodulating properties

“…The described correlation is also in line with recent observations indicating as the successful inhibition of HCV‐miR‐122 in vivo results in NK cell functions normalization . These encouraging findings strongly support the use of exosome‐associated miR‐122‐5p not only as predictor of sustained virological response (SVR) but also of immune restoration.…”

Epigenetic changes and their implications in autoimmune hepatitis

“…Histone modifications are influenced by enzymes including the histone deacetylases (HDCAs), histone acetyltransferases (HATs), histone methyltransferases (HMTs), histone demethylases and the PAD enzyme family [69,83,[85][86][87][88]. MiRNAs can be manipulated by antisense oligonucleotides that inactivate mRNA before translation to miRNAs [226,227] and by epigenetic modifications of methylation-sensitive genes that express the miRNAs [109,110,131,132]. All elements have been manipulated in experimental models of immune-mediated and malignant diseases [33,43,70,126,228,229].…”

The Clinical Application of MicroRNAs in Infectious Disease

“…A small number of patients (3 out 28) had a sustained antiviral response at 76 weeks and phase II trials are planned to see whether combining RG-101 with virus targeting antiviral agents augments HCV therapy. Interestingly RG-101 appeared to increase NK-cell frequency and reduce activation which may have contributed to control of HCV ( 196 ). The hope is a treatment like RG-101 could shorten current HCV treatment regimens or offer an alternative treatment option in patients who have not responded to standard therapies ( 195 ).…”