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: 9769128
• 负责人: Donald G Phinney
• 金额: $ 80.59万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769128
• 关键词: Acute; Acute Lung Injury; Address; Adult Respiratory Distress Syndrome; Age; Agreement; Aliquot; Animal Disease Models; Anti-inflammatory; 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; Therapeutic; Universities; base; clinical effect; clinical efficacy; clinical predictors; clinically relevant; design; 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; 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.

项目摘要 采用间充质干细胞（MSC）的基于细胞的疗法现在覆盖早期至晚期的光谱 行业和学术赞助研究的阶段临床试验，用于广泛无关的医学 状况。尽管基于MSC的临床试验对某些患者产生了重大好处，但其他试验具有 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的主要终点 科学上是有道理的。有效基于MSC的临床疗法发展的一个限制因素是 缺乏在MSC分离效率上分离临床相关差异的指标缺乏指标 制造业，这是为每个患者群体提供优化方案所必需的。因此， 识别和减少可部署生物标志物/指标的实践，这些定义MSC产品基于 迫切需要效力而不是表型或物质组成，以提高可预测性， 目前正在使用的基于MSC的疗法的功效和可重复性。 为了满足这一需求，我们开发了同时的临床指示预测（剪辑）量表 根据人类的内在生物学活性对人类的MSC供体人群进行分类，并预测培养 扩展协议改变了这些人群的组成和功能。剪辑量表的基础是 植根于转录因子Twist1的活性，我们显示了协调的调节 MSC中的茎/祖细胞和旁分泌功能。重要的是，twist1表达的固有水平，它们有所不同 在人类MSC供体人群之间显着预测了促血管生成的抗差异 这些人群的炎症和免疫调节活性，如相关细胞测定中确定的 和急性肺损伤模型。在此应用程序中，我们建议直接测试夹子量表的临床实用性 通过证明其调和对患者的人类MSC分离株的生物学活性的能力 通过回顾性分析，在三个不同完成的人类临床试验中的患者结局。我们也会 使用夹子量表评估CGMP制造方案如何改变组成和生物活性 人类MSC，并利用这些发现来设计新方案，以生成定义效力的MSC 不同的疾病适应症。最后，我们建议确定扩大范围并增强范围的其他指标 剪辑量表的预测值。这些研究的成功完成将提供潜在的 在基于MSC的疗法的设计和制造中使用的变革性指标预计将极大地 增强此类疗法对各种疾病适应症的功效和可重复性。