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

项目摘要 采用间充质干细胞（MSC）的基于细胞的疗法现在涵盖了从早期到晚期的范围。 在行业和学术赞助的研究中进行的临床试验，用于广泛的非相关医学研究。 条件虽然基于MSC的临床试验已经为一些患者带来了显著的益处，但其他试验 产生了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， 在科学上是合理的开发有效的基于MSC的临床疗法的限制因素是 缺乏指标来区分MSC分离物在治疗前和治疗后的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 识别和减少可部署的生物标志物/度量的实践，所述生物标志物/度量定义MSC产品， 迫切需要的是效力而不是物质的表型或组成来提高可预测性， 目前使用的基于MSC的疗法的有效性和可重复性。 为了满足这一需求，我们开发了临床适应症预测（CLIP）量表， 根据其内在生物活性对人类MSC供体群体进行分类，并预测培养- 扩增方案改变了这些群体的组成和功能。CLIP量表的基础是 我们已经证明，转录因子TWIST 1协调调节 干/祖细胞和旁分泌功能。重要的是，TWIST 1表达的内在水平， 在人MSC供体群体之间显著，预测了促血管生成，抗血管生成， 这些群体炎症和免疫调节活性，如在相关的基于细胞的测定中测定的 和急性肺损伤模型。在本申请中，我们建议直接测试CLIP量表的临床实用性 通过证明其能够调和给予患者的人MSC分离物的生物活性 通过回顾性分析在三个不同的已完成的人类临床试验中的患者结局。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，以产生具有确定效力的MSC， 不同的疾病适应症。最后，我们建议确定扩大范围和增强 CLIP量表的预测值。成功完成这些研究将提供一个潜在的 这是一个变革性的指标，其在基于MSC的疗法的设计和制造中的使用预计将大大 增强了这种疗法对各种疾病适应症的功效和可重复性。

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.