Efficient drug development through better insights into functional biomarkers

Our liver fibrosis biomarker panel can be used to rapidly diagnose the individual stages of fibrosis (F0-F4) in patients with metabolic dysfunction-associated steatohepatitis (MASH). The panel utilises serum samples, eliminating the need for liver biopsy for diagnosis. This not only accelerates disease detection, but can enable the accurate identification of patients in each stage for clinical trials.

In our efforts to improve the translatability of preclinical efficacy models, we have developed and validated novel biomarker sets for in vitro, ex vivo, and in vivo preclinical studies. These sets inform on organ-specific disease processes (e.g., vascular inflammation, hepatic inflammation, inflamed adipose tissue, etc.) or critical organ function (e.g., hepatic de novo lipogenesis, gut leakage, mitochondrial dysfunction, oxidative stress, neuronal death, muscle health, etc.). We also have biomarker sets that can indicate susceptibility for the development of disease, including lipid biomarkers for cardiovascular disease and immune biomarkers for respiratory distress syndrome and Long Covid.

We have established validated and robust analytical panels for simultaneous measurement of multiple readouts, including protein multiplex, lipidomics, and metabolomics. This provides even more accurate translation from preclinical to clinical read-outs and informs on entire disease pathways. We have also established generic metabolomics panels to profile short chain fatty acids, bile acids, tryptophan metabolism, or biogenic amines, amongst others. These are also relevant for functional studies of single microorganisms and for microbiota studies.

Among other possibilities, we can develop biomarker analyses in fecal samples (e.g., immune profiling in infant nutrition studies), saliva samples (e.g., stress and inflammation readouts incl. cortisol, cytokines), and breast milk (e.g., immune health, cytokines). Most of TNO’s functional biomarkers can also be measured in organ or tissue homogenates of, for instance, specific regions of the brain (e.g., hippocampus), the gut, or liver tissue. Matrix effects for the various organs were determined and biomarker analyses can thus be performed very rapidly. Also, all listed functional assays can be used for in vitro studies (e.g., primary hepatocytes, stellate cells).

Using 14C tracer compounds and AMS technology, TNO has established many functional biomarkers to measure metabolic fluxes very accurately. Among the unique assays is a flux assay for de novo lipogenesis (14C-acetate is incorporated into C16:0 and then secreted as VLDL) and de novo cholesterol synthesis, as well as reverse cholesterol transport (via HDL) and other assays to measure lipid metabolism fluxes.