Frontiers in Preclinical Safety Biomarkers

Abstract

The measurement of plasma microRNAs (miRNAs) and messenger RNAs (mRNAs) is the most recent effort to identify novel biomarkers in preclinical safety. These genomic markers often display tissue-specific expression, may be released from the tissues into the plasma during toxic events, change early and with high magnitude in tissues and in the blood during specific organ toxicities, and can be measured using multiplex formats. Their validation as biomarkers has been challenged by the technical difficulties. In particular, the concentration of miRNAs in the plasma depends on contamination by miRNAs originating from blood cells and platelets, and the relative fraction of miRNAs in complexes with Argonaute 2, high-density lipoproteins, and in exosomes and microvesicles. In spite of these hurdles, considerable progress has recently been made in assessing the potential value of miRNAs in the clinic, especially in cancer patients and cardiovascular diseases. The future of miRNAs and mRNAs as biomarkers of disease and organ toxicity depends on our ability to characterize their kinetics and to establish robust collection and measurement methods. This review covers the basic biology of miRNAs and the published literature on the use of miRNAs and mRNAs as biomarkers of specific target organ toxicity.

Differentially circulating miRNAs after recent osteoporotic fractures can influence osteogenic differentiation

“…An interpretation of observed changes in circulating miRNAs is often difficult, since the majority of circulating miRNAs is expressed ubiquitously and cannot be precisely matched to a certain tissue. However, tissuespecific miRNAs have been identified [40,41] and shown to contain valuable information about localized aberrant tissue functions and proposed as novel markers of organ toxicity [42]. In the case of the miRNAs reported in this study, let-7g-5p, miR-10a/b and miR-22-3p are ubiquitously expressed, thus, it is not clear whether the changes reported in this study are due to aberrant expression in bone tissue.…”

A Comparative Study of Serum Exosome Isolation Using Differential Ultracentrifugation and Three Commercial Reagents

“…While R 2 values support the existence of an overall linear correlation between miRNA concentration and serum starting volume, a lower serum starting volume did not guarentee a lower miRNA concentration in our data. This disproportionate relationship that we observed between the concentration of particles and the concentration of miRNAs is probably due to the heterogeneity of exRNA distributions across the exosome populations and the potential contamination of non-exosome particles including high-density lipoproteins and RNA binding proteins (argonautes 1 and 2) aggregates [54, 74–76]. …”

Non-proliferative and Proliferative Lesions of the Cardiovascular System of the Rat and Mouse

“…Serum proteins that report myocellular necrosis (cardiac troponins, creatine kinase, myoglobin, fatty acid binding protein) or myocardial wall stress (natriuretic peptides) can be applied non-clinically or clinically (Clements et al 2010; Walker 2006). Circulating nucleic acids are a focus of current interest departing from traditional protein-focused assays (Mikaelian et al 2013). Electrocardiograms (ECGs) are commonly used to detect electrical conductance abnormalities, and a variety of imaging modalities are available for assessing changes in cardiac structure or contractile function (Casartelli et al 2011; French et al 2010; Guth et al 2009).…”