Circulating Biomarkers of Central Nervous System Damage: Translating Preclinical Endpoints to Clinical Outcomes
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Neurotoxicity has been linked to exposure to a number of common drugs and chemicals, yet efficient and minimally-invasive methods for prediction of neurological changes are lacking. Fluid-based biomarkers such as those found in serum, plasma, urine, and cerebrospinal fluid (CSF) have great potential due to the relative ease of sampling, but data on their expression and clinical translation are lacking or inconsistent. Here, we present preclinical data on biomarkerss that have some promise for detection and characterization of neurotoxicity and validate such data for their predictive potential. Trimethyltin is known to cause CNS neuropathology in species from mouse to man. A single dose of trimethyltin, TMT (7 mg/kg, ip) to the rat, led to significant alterations in lipid homeostasis, circulating interleukins and related factors, and markers of neuroinflammation in CSF, serum, plasma and urine. A significant correlation of these fluid biomarkers was observed with traditional neuropathology and magnetic resonance imaging (MRI) endpoints that served to define TMT-induced neurotoxicity. Our data demonstrate a novel correlations of several potential neurotoxicity biomarkers and MRI-based endpoints with TMT-induced neuropathology. These findings suggest of an involvement of specific pathways that can be assessed using peripheral fluids in a preclinical model. A clinical translation of these findings can be investigated by analyzing a blood-based safety biomarker panel of five nervous system-derived proteins in the serum of healthy volunteers and of patients with neurological disorders. GFAP, UCH-L1, NFL, pNFH and Tau will be measured in the serum (or plasma if appropriate) of patients with multiple sclerosis (MS), with non-inflammatory traumatic brain injury (TBI) and of patients undergoing chemotherapy (chemobrain). Data will be compared with the ranges in serum samples from healthy volunteers. In addition, these proteins will also be measured in the CSF of MS and TBI patients to enable possible correlations with serum data. If successful, regulatory qualification of GFAP, UCH-L1, NFL, pNFH and Tau as fluid-based safety biomarkers of drug-induced neurotoxicity will add to a better insight into the underlying mechanisms of neurotoxicity and its early detection, and to the safety of healthy volunteers in phase I clinical trials and patients treated with potentially neurotoxic drugs. Disclaimer: This presentation does not represent EPA, FDA or CDC policy.