Liver disease is a leading cause of patient morbidity and mortality and liver toxicity is a significant impediment to the development of new medicines. Currently the prediction of acute and chronic liver injury in hampered as current biomarkers offer poor clinical/preclinical concordance, staging of injury severity and lack a fundamental mechanistic basis. Consequently, a significant number of animals are required to assess this robustly.
Our hypothesis is that an integrated apprcoh of mechanistic and imaging biomarkers will permit the more sensitive and specific assessment of liver injury and repair. Moreover, this strategy using paired and sequential measurements in the same animal over time will result in a major reduction in animals used and an increase in statistical robustness We have an established interest in the development of new liver injury biomarkers that are translational between preclinical models and human. We have previously demonstrated that a panel of blood based biomarkers with enhanced liver specificity (miR122) and that cover mechanistic insights (Keratin 18; apoptosis/necrosis. HMGB1; inflammation) outperform current clinical chemistry measurements in preclinical studies and in prospective human studies.
Moreover, in 2016 regulatory agencies published letters of support for the further qualification of these biomarkers and encouraged their uptake and application in early preclinical and clinical liver safety studies. However, this biomarker panel is predominantly compromised of analytes that reflect cell death mode or inflammatory processes and lacks novel mechanisms for determining liver function, a key determinant for assessing the severity of liver disease. Idocyanine green (ICG) is a regulatory approved dye whose clearance is dependent on biliary transport through the hepatocyte and can therefore be used to monitor liver function. Multispectral Optoacoustic Tomography (MSOT) and our patented transcutaneous photodiode backpack device are novel imaging modalities that can be used to quantify ICG clearance kinetics as a direct non-invasive measurement of hepatic function. Magnetic Resonance (MR) imaging provides a valuable tool to investigation liver size and inflammation whilst the expression and function of important biological molecules can be monitored in real time by bioluminescence.
We now aim to integrate novel mechanistic biomarkers of liver injury with non-invasive imaging modalities, such as MSOT, MR and bioluminescence to assess liver injury and repair in the same mouse when subject to well established liver disease inducing protocols that have relevance to human health. We will assess whether this approach will permit the more sensitive and specific assessment of liver injury and repair than established methods and we will evaluate its impact on reducing animals numbers as sequential measurements will be performed in the same animal over time.