CERSI Collaborator:  Kathleen Gabrielson, DVM, PhD, DACVP; Cory Brayton, DVM, DACVP, DACLAM

FDA Collaborators:    Kristina Howard, DVM, PhD; Rodney Rouse, DVM, MBA, PhD

Project Start Date: September 2018

 

Regulatory Science Challenge

The FDA is assessing the ability of mouse models that have human components (chimeric) to predict human clinical drug toxicities, immune reactions, and metabolism compared to existing preclinical models. The goal of improved predictivity is to minimize serious unanticipated adverse reactions in early clinical trials that can result in injury, or in rare cases, death of healthy human volunteers. These mouse models may also lead to early identification of adverse events that are currently only recognized after a drug has been marketed and many people exposed. Although chimeric mice have been created for a number of years, the degree of human components, the complexity, and the utility of the models have expanded rapidly. Normal histology (study of tissues at a microscopic level) and histopathological (study of diseased tissues at a microscopic level) responses in these models have only been partially described. Due to this reason, many groups developing these models rely mainly on chemistry and immunoassays (protein detection methods based on its capacity to act as an antigen) for reporting results. This collaboration involves the assessment of tissues from chimeric mice by pathologists previously experienced in the histology, pathology (study of the causes and effects of a disease), and histopathology of common mouse strains, chimeric models, and clinical samples. Data generated from this project will serve as a resource for FDA and drug developers to evaluate the use of these models for drug development and regulatory decision making.

Project Description & Goals

The overall goal of this project is to create a knowledge base for the normal histology and histopathological responses to drugs in chimeric mice. This will be accomplished through the compilation of a histology, pathology, and histopathology atlas for these models. This collaborative effort will provide consistent expert pathology/histopathology support for ongoing FDA studies to evaluate the ability of chimeric mice to predict the effects of drugs in humans.

Research Outcomes/Results

BLT-Immune Humanized Mice as a Model for Nivolumab-Induced Immune-Mediated Adverse Events: Comparison of the NOG and NOG-EXL Strains. Toxicol Sci. 2019 May 1;169(1):194-208. https://www.ncbi.nlm.nih.gov/pubmed/30850839