DDT-BMQ-000109, Qualification of biomarkers for in vitro developmental toxicity screening in a human system

DDT-BMQ-000109，人体系统体外发育毒性筛选生物标志物的资格

• 批准号: 10836889
• 负责人: Jessica A Palmer
• 金额: $ 24.99万
• 依托单位: STEMINA BIOMARKER DISCOVERY, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10836889
• 关键词: DDT; BMQ; 000109; Qualification; biomarkers

Project Summary/Abstract Stemina Biomarker Discovery, Inc. (Stemina) has developed an in vitro human pluripotent stem cell-based assay, devTOX quickPredict (devTOXqP), that uses a biomarker ratio of ornithine to cystine to predict if a compound has the potential to cause developmental toxicity over a wide range of exposures. The goal of this U01 cooperative agreement project is to qualify the devTOXqP assay’s metabolite ratio of ornithine to cystine (o/c ratio) through the Center for Drug Evaluation and Research (CDER) Biomarker Qualification Program (BQP). Stemina has an accepted Letter of Intent (LOI) to qualify the devTOXqP o/c ratio as a safety biomarker for detecting human developmental toxicity potential in vitro using human induced pluripotent stem (iPS) cells at the nonclinical stage of drug development for small molecule drugs as part of a weight-of-evidence assessment as described in the ICH S5(R3) guideline recently issued by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). In Aim 1, we plan to conduct a fit-for-purpose analytical method validation study for the ultra-performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS) method used for measuring the o/c ratio to assess the precision, sensitivity, specificity, dilution linearity, reinjection reproducibility, extraction recovery, and sample carryover of the UPLC-HRMS analytical method. We also plan to measure test article concentrations and characterize test compound stability in the cell culture medium for a subset of the test compounds used in determining the relevance of the biomarker (Aim 5). A prospective qualification study will be conducted to: (1) determine the within-laboratory repeatability and reproducibility of the o/c ratio, (2) evaluate the reliability of the o/c ratio in multiple human iPS cell lines based on prediction concordance and the correlation of response to compound exposure, and (3) assess the relevance of the o/c ratio for predicting developmental toxicity potential across a broad range of pharmaceutical compounds (Aims 2, 3 and 6). Finally, we plan to establish a transfer plan with Stemina’s distribution partner to assess between-laboratory transferability and reliability of the of the devTOXqP standard operating procedures for the inter-laboratory portion of the Qualification Plan (Aim 4). Stemina’s partner will provide financial support for its part of the Qualification Plan. The studies proposed in this grant, and the in-kind support of Stemina’s distribution partner, will provide the necessary data for completing the studies described in the Qualification Plan (once approved) and submitting the Full Qualification Package. While in vitro assays such as devTOXqP will never entirely replace animals when used alone, these assays can reduce the number of compounds tested in animals. The assay may also replace the need for a second species in certain categories of compounds when used as part of a weight of evidence approach as described in the S5 (R3) guideline. Qualification of the devTOXqP assay for developmental toxicity assessment will reduce animal use and provide a human-based assessment of developmental toxicity, ultimately leading to safer drugs and fewer birth defects from chemical exposure in utero.

项目摘要/摘要 Stemina Biomarker Discovery，Inc。（STEMINA）已经开发了一种体外人类多能干细胞 测定，DevTox Quick Predict（DevToxQP），使用Ornithine与Cystine的生物标志物比预测是否是A 化合物有可能在广泛的暴露范围内引起发育毒性。目标的目标 U01合作协议项目是为了鉴定DevToxQP测定法的代谢物比鸟氨酸的代谢物比（O/C 比率）通过药物评估与研究中心（CDER）生物标志物资格计划（BQP）。 STEMINA有一封公认的意向书（LOI），可以将DevToxQP O/C比率作为安全生物标志物的资格 使用人类诱导多能茎（IPS）细胞在体外检测人类发育毒性潜力 小分子药物的非临床药物开发阶段，作为证据评估的一部分 国际技术协调委员会最近发布的ICH S5（R3）指南中描述了 对人类使用的药物（ICH）的要求。在AIM 1中，我们计划进行拟合的分析 超出性液相色谱高分辨率质谱法的方法验证研究 （UPLC-HRMS）用于测量O/C比以评估精度，灵敏度，特异性，稀释的方法 UPLC-HRMS分析的线性，重新注射可重复性，提取恢复和样品结转 方法。我们还计划测量测试文章浓度并表征细胞中的测试复合稳定性 用于确定生物标志物相关性的测试化合物子集的培养基（AIM 5）。 前瞻性资格研究将进行：（1）确定实验室内的可重复性和 O/C比的可重复性，（2）评估基于多个人IPS细胞系中O/C比的可靠性 预测一致性和对复合暴露的反应的相关性，以及（3）评估的相关性 O/C比率预测广泛的药物化合物的发育毒性潜力 （目标2、3和6）。最后，我们计划与Stemina的分销合作伙伴建立转会计划以评估 设施之间的可转让性和DevToxQP标准操作程序的可靠性 资格计划的实验室间部分（AIM 4）。 Stemina的合作伙伴将为其提供财政支持 资格计划的一部分。这项赠款提出的研究以及对Stemina分销的实物支持 合作伙伴将提供必要的数据，以完成资格计划中描述的研究（一次） 批准）并提交完整的资格包。而诸如devtoxqp之类的体外测定将永远不会 这些测定法可以完全替代动物，可以减少动物中测试的化合物的数量。 当用作某些类别的化合物中，该测定法还可以取代对第二种的需求 S5（R3）指南中所述的多种证据方法的一部分。 DEVTOXQP分析的资格 为了进行发育毒性评估，将减少动物的使用，并提供基于人类的评估 发育毒性，最终导致了更安全的药物，并且在子宫内化学暴露较少。