title: Paving the Route to Plasma miR-208a-3p as an Acute Cardiac Injury Biomarker: Preclinical Rat Data Supports Its Use in Drug Safety Assessment.
abstract: Drug-induced cardiac injury (DICI) detection remains a major safety issue in drug development. While circulating microRNAs (miRs) have emerged as promising translational biomarkers, novel early detection biomarkers of cardiotoxicity are needed. This work aims at evaluating whether a panel of putative cardiac injury plasma miRs could serve as early DICI biomarkers in a 4-day rat preclinical model. Out of a panel of 68 selected targets, we identified plasma miR-208a-3p as being significantly upregulated after single administration with either isoproterenol (ISO) or allylamine (AAM). This provides the first evidence of miR-208a-3p detection after AAM administration. Moreover, similarly to cardiac troponins (cTn), plasma miR-208a-3p expression profile appears to be compound-specific with most significant early changes occurring in ISO-treated rats. Overall, miR-208a-3p performance in detecting the severity of myocardial injury, as well as the magnitude of miR-208a-3p increase after ISO or AAM administration, were comparable to that of cTn. Our results highlight the importance of assessing the whole time-dependent profiles of miR expression. Hence, time course evaluation revealed plasma miR candidates whose expression was not stable across the duration of the study in the vehicle group, restricting their utility as cardiac injury-specific biomarkers. In light of these findings, miR-208a-3p has a potential to complement the existing biomarkers of cardiac injury specifically in the context of evaluating toxicity in a time-dependant manner. Assessment of miR-208a-3p in other DICI settings would strengthen its robustness as an early detection biomarker leading to a warranted extensive and rigorous validation.
authors.affiliation: *Investigative Toxicology, Non-Clinical Development, UCB Biopharma SPRL, Chemin du Foriest 1, B-1420 Braine L'Alleud, Belgium andre.dacosta@ucb.com.
authors.forename: Stéphanie F
authors.initials: SF
authors.lastname: Glineur
authors.affiliation: *Investigative Toxicology, Non-Clinical Development, UCB Biopharma SPRL, Chemin du Foriest 1, B-1420 Braine L'Alleud, Belgium.
authors.forename: Pierrette
authors.initials: P
authors.lastname: De Ron
authors.affiliation: Bio Data Analysis, New Medicines Therapeutics, UCB Biopharma SPRL, Chemin du Foriest 1, B-1420 Braine L'Alleud, Belgium.
authors.forename: Etienne
authors.initials: E
authors.lastname: Hanon
authors.affiliation: *Investigative Toxicology, Non-Clinical Development, UCB Biopharma SPRL, Chemin du Foriest 1, B-1420 Braine L'Alleud, Belgium.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Valentin
authors.affiliation: *Investigative Toxicology, Non-Clinical Development, UCB Biopharma SPRL, Chemin du Foriest 1, B-1420 Braine L'Alleud, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Dremier
authors.affiliation: *Investigative Toxicology, Non-Clinical Development, UCB Biopharma SPRL, Chemin du Foriest 1, B-1420 Braine L'Alleud, Belgium andre.dacosta@ucb.com.
authors.forename: André
authors.initials: A
authors.lastname: Nogueira da Costa
mesh_terms: D000208:Acute Disease; D000499:Allylamine / Q000633:toxicity; D000818:Animals; D015415:Biomarkers / Q000097:blood; D066126:Cardiotoxicity / Q000097:blood / Q000175:diagnosis*; D007545:Isoproterenol / Q000633:toxicity; D008297:Male; D035683:MicroRNAs / Q000097:blood*; D051381:Rats; D017208:Rats, Wistar; D019210:Troponin I / Q000097:blood; D020107:Troponin T / Q000097:blood
chemical_list: D015415:Biomarkers; C569395:MIRN208 microRNA, rat; D035683:MicroRNAs; D019210:Troponin I; D020107:Troponin T; D000499:Allylamine; D007545:Isoproterenol
keywords: biomarkers; cardiotoxicity; miR-208a-3p; preclinical; time-dependent profiling