Abstract
We are excited to share this special issue of Toxicologic Pathology, where we focused on the application of molecular pathology to the displine of toxicologic pathology. Nonclinical studies play a critical role in safety risk assessment during drug development and in understanding the human and animal health risks associated with nonpharmaceutical chemicals. The overall success rate of research and development concepts, be it a therapeutic hypothesis, target, molecule or chemical, has been historically low due to a variety of reasons, including putative and actual safety risks. Histopathologic observations suggestive of toxicity and/or adverse effects are often seen in the course of exploratory toxicology and nonclinical safety studies. However, the underlying toxicologic mechanisms and their translational relevance to human health is not always well-understood. The advent of molecular pathology assays could bridge this gap and allow us to better understand the nature of histopathologic findings and make better recommendations about safety risk. Unfortunately, a perceived lack of reliability, rigor, reproducibility, and/or standardization of these assays has inhibited their broader application in the field of toxicologic pathology. Owing to the persistence and vision of the scientific community, significant progress has been made to address this gap. Today, we have a wide range of molecular pathology tools that enable us to better understand the mechanisms of toxicity and their relevance to human health. These tools are now being used to identify novel drug targets, model diseases, assess drug efficacy and predict toxicities.
To embrace the ongoing molecular pathology transformation, it is imperative for practicing toxicologic pathologists and pathobiology scientists to stay abreast of the many technological developments in the field and the workflows of a modern pathology laboratory. With this goal in mind, in this special issue on Molecular Pathology, we have curated contemporary reviews on major pathobiology investigative technologies and examples of their application in discovery and investigative toxicology settings. Trends and challenges of the modern pathology laboratory for biopharmaceutical research excellence by Siso et al., sets the pace by detailing the current state and future vision for excellence in research pathology. Understanding the biodistribution and pharmacodynamics of oncolytic virus in nonclinical tumor model by Matter et al., derisking histomorphology findings associated with antisense oligonucleotides by Dubost et al., and the use of multiplexed siRNA immunoassay to understand siRNA function, abundance and localization by Ly et al. allow the readers to appreciate real-life examples of how molecular pathology techniques have been applied in the context of safety assessment of some novel modalities. While the manuscript by Vezzali et al. provides an excellent review of the basics and application of mass spectrometry imaging in diagnostic and toxicologic pathology, Chen et al. and Yang et al. demonstrate the application of mass spectrometry imaging in understanding renal and biliary toxicities, respectively. The issue is further enriched by the detailed overview of spatial omics (Hahn et al.), examples on the integration of chromogenic in situ hybridization for target validation (Win et al.), the use of cell-based protein array in preclinical safety assessment of biologics (Vicart et al.), and description of deep learning tool to perform enhanced histopathology evaluation of spleen without using immunohistochemistry (Mehrvar et al.).
The past few decades have seen massive growth in the development and application of molecular pathology technologies in basic research and in drug discovery and development. We recognize the potential for these techniques to greatly enhance the discipline of toxicologic pathology, particularly in the areas of target discovery and expression profiling, pharmacokinetics, spatial biodistribution, and mechanistic investigations. These technologies are impactful, opening new dimensions of knowledge, and rapidly evolving, compelling us to promote awareness, continued education, and scientific outreach to assure that these methods are applied according to sound scientific principles. We thank you, the contributing authors and the readers for your devotion to the growth of knowledge and technology in this field.
