Vlasakova Katerina, Tsuchiya Takayuki, Garfinkel Ivy N, Ruth Michael P, Tyszkiewicz Cheryl, Detwiler Theodore J, Somps Christopher J, Di Cesare Mannelli Lorenzo, Glaab Warren E
Merck & Co., Inc., Rahway, NJ, United States.
Drug Safety Research and Development, Pfizer, Groton, CT, United States.
Front Neurosci. 2024 Jan 16;17:1285359. doi: 10.3389/fnins.2023.1285359. eCollection 2023.
Target organ toxicity is often a reason for attritions in nonclinical and clinical drug development. Leveraging emerging safety biomarkers in nonclinical studies provides an opportunity to monitor such toxicities early and efficiently, potentially translating to early clinical trials. As a part of the European Union's Innovative Medicines Initiative (IMI), two projects have focused on evaluating safety biomarkers of nervous system (NS) toxicity: Translational Safety Biomarker Pipeline (TransBioLine) and Neurotoxicity De-Risking in Preclinical Drug Discovery (NeuroDeRisk).
Performance of fluid-based NS injury biomarker candidates neurofilament light chain (NF-L), glial fibrillary acidic protein (GFAP), neuron specific enolase (NSE) and total Tau in plasma and cerebrospinal fluid (CSF) was evaluated in 15 rat studies. Model nervous system toxicants as well as other compounds were used to evaluate sensitivity and specificity. Histopathologic assessments of nervous tissues and behavioral observations were conducted to detect and characterize NS injuries. Receiver operator characteristic (ROC) curves were generated to compare the relative performance of the biomarkers in their ability to detect NS injury.
NF-L was the best performer in detecting both peripheral nervous system (PNS) and CNS injury in plasma, (AUC of 0.97-0.99; respectively). In CSF, Tau correlated the best with CNS (AUC 0.97), but not PNS injury. NSE and GFAP were suitable for monitoring CNS injury, but with lesser sensitivity. In summary, NF-L is a sensitive and specific biomarker in rats for detecting compound-induced central and peripheral NS injuries. While NF-L measurement alone cannot inform the site of the injury, addition of biomarkers like Tau and NSE and analysis in both blood and CSF can provide additional information about the origin of the NS injury.
These results demonstrate the utility of emerging safety biomarkers of drug-induced NS injury in rats and provide additional supporting evidence for biomarker translation across species and potential use in clinical settings to monitor drug-induced NS injury in patients.
靶器官毒性常常是临床前和临床药物研发中导致药物研发失败的原因。在临床前研究中利用新兴的安全性生物标志物提供了一个早期且高效监测此类毒性的机会，这有可能转化应用于早期临床试验。作为欧盟创新药物计划（IMI）的一部分，有两个项目专注于评估神经系统（NS）毒性的安全性生物标志物：转化安全性生物标志物管道项目（TransBioLine）和临床前药物发现中的神经毒性风险降低项目（NeuroDeRisk）。
在15项大鼠研究中评估了血浆和脑脊液（CSF）中基于液体的NS损伤生物标志物候选物神经丝轻链（NF-L）、胶质纤维酸性蛋白（GFAP）、神经元特异性烯醇化酶（NSE）和总 Tau 的性能。使用模型神经系统毒物以及其他化合物来评估敏感性和特异性。对神经组织进行组织病理学评估并进行行为观察，以检测和表征NS损伤。生成受试者操作特征（ROC）曲线以比较生物标志物在检测NS损伤能力方面的相对性能。
NF-L在检测血浆中的外周神经系统（PNS）和中枢神经系统（CNS）损伤方面表现最佳，（AUC分别为0.97 - 0.99）。在脑脊液中，Tau与中枢神经系统相关性最佳（AUC为0.97），但与外周神经系统损伤无关。NSE和GFAP适用于监测中枢神经系统损伤，但敏感性较低。总之，NF-L是大鼠中检测化合物诱导的中枢和外周NS损伤的敏感且特异的生物标志物。虽然仅NF-L测量无法告知损伤部位，但添加Tau和NSE等生物标志物并在血液和脑脊液中进行分析可以提供有关NS损伤起源的额外信息。
这些结果证明了药物诱导的大鼠NS损伤新兴安全性生物标志物的实用性，并为跨物种生物标志物转化以及在临床环境中监测患者药物诱导的NS损伤的潜在用途提供了额外的支持证据。
