SBIR Phase I: Cell-derived vesicles loaded with novel anti-inflammatories for treatment of severe COVID-19

这项小型企业创新研究（SBIR）第一阶段项目的更广泛影响/商业潜力是为患有危及生命的医疗并发症的COVID-19患者提供一种新的治疗选择。冠状病毒感染会引起炎症反应，导致急性呼吸窘迫综合征、肺部和器官衰竭。该项目建立在新方法的基础上，产生细胞衍生的药物递送载体，当与特殊分子结合时，特异性靶向炎症组织并改变疾病进程。这种候选药物还可以影响许多疾病的结果，其中失控的炎症是疾病病理学的基础，例如新出现的病毒和/或细菌威胁，神经系统疾病，如阿尔茨海默病和帕金森病，中风和心脏病发作，自身免疫性疾病，包括狼疮和关节炎，以及各种癌症。这个小企业创新研究第一阶段项目使用新技术，利用施加到培养细胞上的物理和化学力来产生细胞衍生的囊泡。与最先进的技术相比，该技术产生的囊泡在产品产率、产生速率和均匀性方面有实质性的改进，并且允许控制囊泡的大小。此外，可以从任何细胞系产生囊泡，以优化囊泡对体内特定组织的向性。当装载有诱导炎症消退的分子如消退素时，这些囊泡可以产生新的治疗方法。拟议的工作将优化囊泡生产，进行囊泡表征，并制定有效的resolvin加载程序。随后将评估细胞和肺损伤动物模型中的组织特异性递送和功能。体外试验将测量囊泡特异性结合同源受体并阻断中性粒细胞迁移和巨噬细胞产生促炎介质的能力。该疾病模型将监测载有消退素的囊泡阻断和逆转肺部炎症的能力。这一潜在的三重活动可能会产生一种替代的治疗方式。该奖项反映了NSF的法定使命，并被认为是值得通过使用基金会的知识价值和更广泛的影响审查标准进行评估的支持。

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase I project is to provide a novel treatment option for COVID-19 patients with life-threatening medical complications. Coronavirus infection causes inflammatory reactions leading to acute respiratory distress syndrome, lung and organ failure. This project builds on new methods to generate cell-derived drug delivery vehicles that, when combined with special molecules, specifically target inflamed tissues and modify the disease course. This drug candidate could also impact the outcome of many diseases where runaway inflammation underpins disease pathology, such as emerging viral and/or bacterial threats, neurological conditions such as Alzheimer’s and Parkinson’s disease, stroke and heart attack, autoimmune disease including lupus and arthritis, and various cancers. This Small Business Innovation Research Phase I project uses new technology that harnesses both physical and chemical forces applied to cultured cells to generate cell-derived vesicles. Compared to state-of-the-art techniques, this technology generates vesicles with substantial improvements in product yield, generation rate, and homogeneity, and allows control over vesicle size. Moreover, vesicles can be generated from any cell line to optimize vesicle tropism for specific tissues in the body. When loaded with molecules that induce inflammation-resolution such as resolvins, these vesicles could yield a new treatment. The proposed work will optimize vesicle production, perform vesicle characterization, and develop efficient resolvin-loading procedures. Tissue-specific delivery and functionality in cells and animal models of lung injury will subsequently be assessed. The in vitro assays will measure the ability of vesicles to specifically bind cognate receptors and block neutrophil migration and macrophage production of pro-inflammatory mediators. The disease model will monitor the capacity of resolvin-loaded vesicles to block and reverse inflammation in the lung. This potential triple activity could generate an alternate treatment modality.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.