Functional Biomarkers for ALS

ALS 功能性生物标志物

• 批准号: 10589932
• 负责人: Heather M. Wilkins
• 金额: $ 18.78万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589932
• 关键词: ANXA5 gene; Age; Algorithms; Amyotrophic Lateral Sclerosis; Apoptosis; Biological; Biological Assay; Biological Markers; Biotechnology; Blood; Blood Platelets; Clinic; Clinical; Clinical Trials; Clinical and Translational Science Awards; Development; Disparity; Enrollment; Enzyme-Linked Immunosorbent Assay; Equation; FDA approved; Future; Health; Individual; Kansas; Letters; Light; Link; Lymphocyte; Measures; Medical center; Membrane Potentials; Missouri; Mitochondria; Modality; Multi-Institutional Clinical Trial; Outcome; Pathologic; Phosphorylation; Plasma; Post-Translational Protein Processing; Protocols documentation; Rare Diseases; Recording of previous events; Sampling; Site; Standardization; Statistical Models; Superoxides; Therapeutic; Therapeutic Clinical Trial; Therapeutic Index; Translational Research; Universities; Validation; Venous blood sampling; amyotrophic lateral sclerosis therapy; axon injury; blood-based biomarker; clinical trial readiness; drug development; frontier; indexing; mitochondrial dysfunction; mitochondrial membrane; neurofilament; neuromuscular; neuroprotection; novel; novel marker; open label; placebo controlled trial; protein TDP-43; protein aggregation; protein expression; proteostasis; recruit; response biomarker; targeted biomarker; therapeutic target; treatment response

Project Summary Functional non-invasive biomarkers are critical for therapeutic target engagement outcomes in progressive rare diseases. Amyotrophic lateral sclerosis (ALS) clinical trial development has an urgent need for functional biomarkers to assess therapeutic response and target engagement. We will fulfill that urgent need. We have a history using functional blood-based biomarkers for clinical trials in ALS. Rasagaline (a neuroprotective compound) showed mitochondrial biomarker target -engagement in an open-labeled trial. A subsequent multi-center placebo-controlled trial failed to replicate target engagement. Disparities among clinical trial outcomes revealed issues with sample handling and the need for a generalized estimating equation (GEE) statistical model. Without the ability to accurately detect target engagement therapeutic opportunities will be lost. ALS pathological features include mitochondrial dysfunction and loss of proteostasis (protein aggregation). Mitochondrial dysfunction and proteostasis are intricately linked biological modalities which are key targets for upcoming clinical trials in ALS. These clinical trials will benefit from our functional biomarkers. We will clinically validate blood based mitochondrial and proteostasis biomarker protocols for use as indices of target engagement in future clinical trials. We will compare mitochondrial and proteostasis biomarkers within ALS and control subjects over eight months. We will develop a GEE statistical model to provide guidance for power calculations in our future planned clinical trials. We will determine biomarker relationships and develop a predictive statistical approach for our novel functional biomarkers.

项目概要 功能性非侵入性生物标志物对于治疗靶点参与结果至关重要 进行性罕见疾病。肌萎缩侧索硬化症（ALS）临床试验开发迫切需要 用于评估治疗反应和目标参与度的功能生物标志物。我们将满足这一迫切需要。 我们拥有使用功能性血液生物标志物进行 ALS 临床试验的历史。雷沙加林 (a 神经保护化合物）在一项开放标记试验中显示线粒体生物标志物靶点参与。一个 随后的多中心安慰剂对照试验未能复制目标参与度。之间的差距 临床试验结果揭示了样本处理的问题以及进行广义估计的必要性 方程（GEE）统计模型。无法准确检测目标参与治疗 机会就会失去。 ALS 病理特征包括线粒体功能障碍和蛋白质稳态丧失（蛋白质 聚合）。线粒体功能障碍和蛋白质稳态是错综复杂地联系在一起的生物模式 即将开展的 ALS 临床试验的关键目标。这些临床试验将受益于我们的功能性生物标志物。 我们将临床验证基于血液的线粒体和蛋白质稳态生物标志物方案，以用作以下指标： 目标参与未来的临床试验。我们将比较线粒体和蛋白质稳态生物标志物 ALS 和对照组受试者超过八个月。我们将开发GEE统计模型，为 我们未来计划的临床试验中的功效计算。我们将确定生物标志物关系并开发 我们的新型功能生物标志物的预测统计方法。