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

项目摘要 使用间充质干细胞(MSCs)的基于细胞的治疗现在涵盖了从早期到晚期的各个阶段 行业和学术赞助研究的阶段临床试验，涉及一系列无关的医学 条件。虽然基于MSC的临床试验对一些患者产生了显著的好处，但其他试验已经 产生次优结果或未能达到其主要疗效终点，即使在治疗的情况下也是如此 这在科学上是很有道理的。以骨髓间充质干细胞为基础的有效临床疗法发展的一个限制因素是 缺乏标准来区分治疗前后MSC分离株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， 确定可部署的生物标记物/指标并将其应用于实践，这些生物标记物/指标基于 要提高可预测性，关键需要的是效力而不是物质的表型或成分， 目前使用的基于MSC的疗法的有效性和重复性。 为了满足这一需求，我们开发了一种临床适应症预测(CLIP)量表，它同时 根据人类骨髓间充质干细胞捐赠者的内在生物活性对其进行分类，并预测培养- 扩张协议改变了这些种群的组成和功能。剪辑比例的基础是 植根于转录因子Twist1的活性，我们已经证明它是协调调节的 MSC的干/祖细胞和旁分泌功能。重要的是，Twist1的内在表达水平有所不同 在人类MSC捐赠者群体之间的显著差异，预测在促血管生成、抗- 在相关的细胞分析中确定这些人群的炎症和免疫调节活性 和急性肺损伤模型。在这个应用中，我们建议直接测试CLIP量表的临床实用性 通过证明它有能力协调给患者使用的人类MSC分离株的生物活性 通过回顾分析在三个不同的完成的人体临床试验中的患者结果。我们还将 使用Clip量表评估cGMP生产方案如何改变成分和生物活性 并利用这些发现来设计新的方案来生成具有特定效力的MSCs 不同的疾病指征。最后，我们建议确定其他指标，以扩大范围和增强 剪辑比例的预测值。成功完成这些研究将带来潜在的 在基于MSC的疗法的设计和制造中使用的变革性指标有望大大 提高这些疗法对各种疾病适应症的有效性和可重复性。

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.