Immune- and miRNA-response to recombinant interferon beta-1a: a biomarker evaluation study to guide the development of novel type I interferon- based therapies

Abstract

BackgroundThe innate immune receptor RIG-I detects viral RNA within the cytosol of infected cells. Activation of RIG-I leads to the induction of antiviral cytokines, in particular type I interferon, the inhibition of a T(H)17 response as well as to the suppression of tumor growth. Therefore, RIG-I is a promising drug target for the treatment of cancer as well as multiple sclerosis. A specific ligand for RIG-I is currently in preclinical testing. The first-in-human trial will need to be carefully designed to avoid an overshooting cytokine response. Therefore, the ResI study was set up to analyze the human immune response to standard treatment with recombinant interferon-beta to establish biomarkers for safety and efficacy of the upcoming first-in-human trial investigating the RIG-I ligand.Methods/DesignResI is a single center, prospective, open label, non-randomized phase I clinical trial. Three different cohorts (20 healthy volunteers, 20 patients with RRMS and ongoing interferon-beta treatment and 10 patients starting on interferon-beta) will receive standard interferon-beta-1a therapy for nine days. The study will be conducted according to the principles of the german medicinal products act, ICH-GCP, and the Declaration of Helsinki on the phase I unit of the Institute of Clinical Chemistry and Clinical Pharmacology and in the Department of Neurology, both University Hospital Bonn. Interferon-beta-induced cytokine levels, surface marker on immune cells, mRNA- and miRNA-expression as well as psychometric response will be investigated as target variables.DiscussionThe ResI study will assess biomarkers in response to interferon-β treatment to guide the dose steps within the first-in-human trial with a newly developed RIG-I ligand. Thus, ResI is a biomarker study to enhance the safety of the clinical development of a first-in-class compound. The data can additionally be used for the development of other therapies based on type I interferon induction such as TLR ligands. Moreover, it will help to understand the interferon-beta induced immune response in a controlled in vivo setting in the human system.Trial registrationclinicaltrials.gov ID NCT02364986

Interferon-beta-induced changes in neuroimaging phenotypes of appetitive motivation and reactivity to emotional salience

“…In a large international cohort study of MS, after exclusion of patients with a previous history of depression, no association between IFN-beta treatment and induction or exacerbation of depressive symptoms was observed (Schippling et al., 2016). However, in the present study, the occurrence of psychopathological symptoms was observed even if participants with a history of depression or depressive symptoms (as assessed by the psychiatric disease diagnostic manual, MINI) were excluded by the admission criteria (Coenen et al., 2015).…”

“…Functional MRI measurements were undertaken as part of the “Immune- and miRNA-response to recombinant IFN-beta in healthy volunteers and patients with relapsing remitting multiple sclerosis” clinical study (trial short title: RESI), listed under EudraCT-number “2012-005475-13” in the EU Clinical Trials Register database (Coenen et al., 2015). The clinical study was conducted at the phase I Unit and the Clinical Study Core Unit of the University Hospital Bonn in accordance with the ICH Guideline for Good Clinical Practice, the relevant national regulations and the Declaration of Helsinki.…”

“…Applying a symptom-dimensional approach, we wanted to investigate phenotypes of depressive psychopathology occurring in healthy volunteers in the early phases of IFN-beta treatment in a functional neuroimaging study (fMRI). The participants were undergoing a study on cytokine responses upon administration of an IFN stimulus for eight consecutive days (Coenen et al., 2015). Two fMRI phenotypes were chosen as representative of two known important aspects of depressive functioning: lack of sensitivity to reward (impairment in appetitive motivation, leading to an anhedonic symptom domain, (Treadway and Zald, 2011)) and hyperreactivity to negative emotional stimuli (Siegle et al., 2002; Stuhrmann et al., 2011; Whalen et al., 2002).…”

The effect of IFN‐β 1a on expression of MDA5 and RIG‐1 in multiple sclerosis patients

“…And it may be the main cause of the downregulation of IFN‐I in the MS patients. An investigation approved the benefits of RIG‐1 ligand in activating the RIG‐1 pathway and the improvement of clinical presentation of MS [19]. Accordingly, it has been shown that using RIG‐1 ligands leads to decreased Th1 and Th17 T‐cell responses within the CNS [20].…”

Precision Medicine in Neurodegenerative Diseases: Some Promising Tips Coming from the microRNAs’ World

“…The first longitudinal study on the miRNA expression changes in response to IFN-β showed that an up-regulation of IFN-β-responsive genes was coupled to a down-regulation of several miRNAs (including members of the miR-29 family) in peripheral blood mononuclear cells (PBMCs) of RRMS patients [78]. The involvement of miRNAs in response to IFN-β was pointed out by a clinical trial, where the participants received standard IFN-β therapy for nine days [79]. Data showed that aberrant expression levels of miR-145 and miR-20a-5p were normalized in the whole blood of RRMS patients treated with IFN-β [80].…”