title: 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: BACKGROUND
  The 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
  ResI 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.
  
  
  CONCLUSIONS
  The 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.
  
  
  BACKGROUND
  clinicaltrials.gov ID NCT02364986.
authors.affiliation: Clinical Study Core Unit, Study Center Bonn (SZB), University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. martin.coenen@ukb.uni-bonn.de.|Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. martin.coenen@ukb.uni-bonn.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Coenen
authors.affiliation: Federal Institute for Drugs and Medical Devices, Kurt-Georg-Kiesinger-Allee 3, 53175, Bonn, Germany. annette-viktoria.hinze@bfarm.de.
authors.forename: Annette Viktoria
authors.initials: AV
authors.lastname: Hinze
authors.affiliation: Federal Institute for Drugs and Medical Devices, Kurt-Georg-Kiesinger-Allee 3, 53175, Bonn, Germany. martin.mengel@bfarm.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Mengel
authors.affiliation: Clinical Study Core Unit, Study Center Bonn (SZB), University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. christine.fuhrmann@ukb.uni-bonn.de.|Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. christine.fuhrmann@ukb.uni-bonn.de.
authors.forename: Christine
authors.initials: C
authors.lastname: Fuhrmann
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. bastian.luedenbach@ukb.uni-bonn.de.
authors.forename: Bastian
authors.initials: B
authors.lastname: Lüdenbach
authors.affiliation: Deparment of Neurology, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. julian.zimmermann@ukb.uni-bonn.de.
authors.forename: Julian
authors.initials: J
authors.lastname: Zimmermann
authors.affiliation: Clinical Study Core Unit, Study Center Bonn (SZB), University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. verena.dykstra@ukb.uni-bonn.de.|Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. verena.dykstra@ukb.uni-bonn.de.
authors.forename: Verena
authors.initials: V
authors.lastname: Dykstra
authors.affiliation: Institute of Medical Biometrics, Informatics and Epidemiology, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. fimmers@imbie.meb.uni-bonn.de.
authors.forename: Rolf
authors.initials: R
authors.lastname: Fimmers
authors.affiliation: Department of Psychiatry and Psychotherapy III, University of Ulm, Ulm, Germany. roberto.viviani@uni-ulm.de.
authors.forename: Roberto
authors.initials: R
authors.lastname: Viviani
authors.affiliation: Federal Institute for Drugs and Medical Devices, Kurt-Georg-Kiesinger-Allee 3, 53175, Bonn, Germany. Julia.Stingl@bfarm.de.
authors.forename: Julia
authors.initials: J
authors.lastname: Stingl
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. stefan.holdenrieder@ukb.uni-bonn.de.
authors.forename: Stefan
authors.initials: S
authors.lastname: Holdenrieder
authors.affiliation: Deparment of Neurology, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. marcus_m.mueller@ukb.uni-bonn.de.
authors.forename: Marcus
authors.initials: M
authors.lastname: Müller
authors.affiliation: Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. gunther.hartmann@ukb.uni-bonn.de.
authors.forename: Gunther
authors.initials: G
authors.lastname: Hartmann
authors.affiliation: Clinical Study Core Unit, Study Center Bonn (SZB), University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. ccoch@uni-bonn.de.|Institute of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Germany. ccoch@uni-bonn.de.
authors.forename: Christoph
authors.initials: C
authors.lastname: Coch
mesh_terms: D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D000368:Aged; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D000068556:Interferon beta-1a / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017063:Outcome Assessment, Health Care; D011446:Prospective Studies; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic; D011994:Recombinant Proteins / Q000627:therapeutic use; D013997:Time Factors; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D007370:Interferon Type I; D035683:MicroRNAs; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000068556:Interferon beta-1a