A Clinical Indications Prediction (CLIP) Scale for Human Mesenchymal Stem Cells

人类间充质干细胞的临床适应症预测 (CLIP) 量表

• 批准号: 10240462
• 负责人: Donald G Phinney
• 金额: $ 18.97万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-04-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240462
• 关键词: Acute; Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Age; Agreement; Aliquot; Animal Disease Models; Anti-Inflammatory Agents; Aspirate substance; Binding; Biological; Biological Assay; Biological Markers; Cell Therapy; Cells; ChIP-seq; Chronic lung disease; Classification; Clinical; Clinical Treatment; Clinical Trials; Colorado; Data; Development; Disease; Donor Selection; Functional disorder; Gene Expression; Genes; Genomics; Goals; Health Status; Human; Human Activities; Immune; Industry; Inflammatory; Investigational Therapies; Laboratories; Marrow; Mediating; Medical; Mesenchymal Stem Cells; Micro Array Data; Minnesota; Modeling; Outcome; Parents; Patient-Focused Outcomes; Patients; Phase; Phenotype; Plant Roots; Population; Predictive Value; Production; Property; Protocols documentation; Reproducibility; Research Personnel; Running; TWIST1 gene; Testing; Universities; base; clinical effect; clinical efficacy; clinical predictors; clinically relevant; design; donor stem cell; exosome; genome-wide; graft vs host disease; human disease; idiopathic pulmonary fibrosis; immunoregulation; improved; multidisciplinary; novel; paracrine; patient population; population based; primary endpoint; progenitor; promoter; research clinical testing; stem; stem cell biology; stem cell population; stem cell therapy; targeted treatment; tool; transcription factor

Project Summary Cell-based therapies employing mesenchymal stem cells (MSCs) now cover the spectrum of early to late phase clinical trials in both industry and academic sponsored studies for a broad array of unrelated medical conditions. While MSC-based clinical trials have yielded significant benefits for some patients, other trials have yielded suboptimal outcomes or failed to meet their primary endpoints of efficacy even in cases were the therapy is well justified scientifically. A limiting factor in the development of efficacious MSC-based clinical therapies is the lack of metrics to discriminate clinically relevant differences in the potency of MSC isolates pre- and post- manufacturing, which is necessary to deliver optimized protocols for each patient population. Therefore, the identification and reduction to practice of deployable biomarkers/metrics that define MSC products based on potency rather than phenotype or composition of matter are critically needed to improve the predictability, efficacy, and reproducibility of MSC-based therapies currently in use today. To address this need, we developed a CLinical Indications Prediction (CLIP) scale that simultaneously classifies human MSC donor populations based on their intrinsic biological activity, and predicts how culture- expansion protocols alter the composition and function of these populations. The basis for the CLIP scale is rooted in the activity of the transcription factor TWIST1, which we have shown coordinately regulates stem/progenitor and paracrine functions in MSC. Importantly, intrinsic levels of TWIST1 expression, which vary significantly between human MSC donor populations, predicts differences in the pro-angiogenic, anti- inflammatory and immuno-modulatory activity of these population as determined in relevant cell-based assays and an acute lung injury model. In this application, we propose to directly test the clinical utility of the CLIP scale by demonstrating its ability to reconcile the biological activity of human MSC isolates administered to patients with patient outcomes in three different completed human clinical trials via retrospective analysis. We will also use the CLIP scale to evaluate how cGMP manufacturing protocols alter the composition and biological activity of human MSCs, and exploit these findings to devise novel protocols to generate MSCs of defined potency for different disease indications. Lastly, we propose to identify additional metrics that expand the scope and enhance the predictive value of the CLIP scale. Successful completion of these studies will deliver a potentially transformative metric whose use in the design and manufacture of MSC-based therapies is anticipated to greatly enhance the efficacy and reproducibility of such therapies for a variety of disease indications.

项目概要 使用间充质干细胞 (MSC) 的细胞疗法现已涵盖早期到晚期的范围 在行业和学术界资助的一系列不相关的医学研究中进行阶段临床试验 状况。虽然基于间充质干细胞的临床试验已经为一些患者带来了显着的益处，但其他试验也给一些患者带来了显着的益处。 即使在治疗的情况下，也产生了次优的结果或未能达到其主要疗效终点 是有充分科学依据的。开发基于 MSC 的有效临床疗法的一个限制因素是 缺乏指标来区分 MSC 分离株前后效力的临床相关差异 制造，这是为每个患者群体提供优化方案所必需的。因此， 识别并减少可部署生物标志物/指标的实践，这些生物标志物/指标定义基于 为了提高可预测性，迫切需要的是效力而不是表型或物质组成， 目前使用的基于 MSC 的疗法的功效和可重复性。 为了满足这一需求，我们开发了临床适应症预测 (CLIP) 量表，同时 根据人类 MSC 供体群体的内在生物活性对其进行分类，并预测培养过程如何 扩张方案改变了这些群体的组成和功能。 CLIP量表的基础是 植根于转录因子 TWIST1 的活性，我们已经证明它可以协调调节 MSC 中的干细胞/祖细胞和旁分泌功能。重要的是，TWIST1 表达的内在水平各不相同 人类 MSC 供体群体之间的差异显着，预测促血管生成、抗血管生成的差异 在相关的基于细胞的测定中确定这些群体的炎症和免疫调节活性 和急性肺损伤模型。在此应用中，我们建议直接测试 CLIP 量表的临床效用 通过展示其协调给予患者的人类 MSC 分离物的生物活性的能力 通过回顾性分析，对三项不同的已完成人体临床试验中的患者结果进行了评估。我们还将 使用 CLIP 量表评估 cGMP 生产协议如何改变成分和生物活性 人类 MSC 的研究，并利用这些发现设计新的方案来生成具有确定效力的 MSC 不同的疾病适应症。最后，我们建议确定额外的指标来扩大范围并增强 CLIP量表的预测价值。成功完成这些研究将带来潜在的 变革性指标，其在基于 MSC 的疗法的设计和制造中的使用预计将极大地促进 提高此类疗法对多种疾病适应症的功效和可重复性。