Lanzoni G, Linetsky E, Correa D, Alvarez R A, Marttos A, Hirani K, Cayetano S Messinger, Castro J G, Paidas M J, Efantis Potter J, Xu X, Glassberg M, Tan J, Patel A N, Goldstein B, Kenyon N S, Baidal D, Alejandro R, Vianna R, Ruiz P, Caplan A I, Ricordi C
Diabetes Research Institute, Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA.
Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
CellR4 Repair Replace Regen Reprogram. 2020;8. doi: 10.32113/cellr4_20204_2839. Epub 2020 Apr 28.
The coronavirus SARS-CoV-2 is cause of a global pandemic of a pneumonia-like disease termed Coronavirus Disease 2019 (COVID-19). COVID-19 presents a high mortality rate, estimated at 3.4%. More than 1 out of 4 hospitalized COVID-19 patients require admission to an Intensive Care Unit (ICU) for respiratory support, and a large proportion of these ICU-COVID-19 patients, between 17% and 46%, have died. In these patients COVID-19 infection causes an inflammatory response in the lungs that can progress to inflammation with cytokine storm, Acute Lung Injury (ALI), Acute Respiratory Distress Syndrome (ARDS), thromboembolic events, disseminated intravascular coagulation, organ failure, and death. Mesenchymal Stem Cells (MSCs) are potent immunomodulatory cells that recognize sites of injury, limit effector T cell reactions, and positively modulate regulatory cell populations. MSCs also stimulate local tissue regeneration via paracrine effects inducing angiogenic, anti-fibrotic and remodeling responses. MSCs can be derived in large number from the Umbilical Cord (UC). UC-MSCs, utilized in the allogeneic setting, have demonstrated safety and efficacy in clinical trials for a number of disease conditions including inflammatory and immune-based diseases. UC-MSCs have been shown to inhibit inflammation and fibrosis in the lungs and have been utilized to treat patients with severe COVID-19 in pilot, uncontrolled clinical trials, that reported promising results. UC-MSCs processed at our facility have been authorized by the FDA for clinical trials in patients with an Alzheimer's Disease, and in patients with Type 1 Diabetes (T1D). We hypothesize that UC-MSC will also exert beneficial therapeutic effects in COVID-19 patients with cytokine storm and ARDS. We propose an early phase controlled, randomized clinical trial in COVID-19 patients with ALI/ARDS. Subjects in the treatment group will be treated with two doses of UC-MSC (l00 × 10 cells). The first dose will be infused within 24 hours following study enrollment. A second dose will be administered 72 ± 6 hours after the first infusion. Subject in the control group will receive infusion of vehicle (DPBS supplemented with 1% HSA and 70 U/kg unfractionated Heparin, delivered IV) following the same timeline. Subjects will be evaluated daily during the first 6 days, then at 14, 28, 60, and 90 days following enrollment (see Schedule of Assessment for time window details). Safety will be determined by adverse events (AEs) and serious adverse events (SAEs) during the follow-up period. Efficacy will be defined by clinical outcomes, as well as a variety of pulmonary, biochemical and immunological tests. Success of the current study will provide a framework for larger controlled, randomized clinical trials and a means of accelerating a possible solution for this urgent but unmet medical need. The proposed early phase clinical trial will be performed at the University of Miami (UM), in the facilities of the Diabetes Research Institute (DRI), UHealth Intensive Care Unit (ICU) and the Clinical Translational Research Site (CTRS) at the University of Miami Miller School of Medicine and at the Jackson Memorial Hospital (JMH).
冠状病毒SARS-CoV-2是一种类似肺炎疾病的全球大流行病因，该疾病被称为2019冠状病毒病（COVID-19）。COVID-19呈现出高死亡率，估计为3.4%。超过四分之一的住院COVID-19患者需要入住重症监护病房（ICU）以获得呼吸支持，并且这些ICU-COVID-19患者中有很大一部分，即17%至46%，已经死亡。在这些患者中，COVID-19感染会在肺部引发炎症反应，这种反应可能会发展为伴有细胞因子风暴、急性肺损伤（ALI）、急性呼吸窘迫综合征（ARDS）、血栓栓塞事件、弥散性血管内凝血、器官衰竭和死亡的炎症。间充质干细胞（MSCs）是具有强大免疫调节作用的细胞，能够识别损伤部位，限制效应T细胞反应，并正向调节调节性细胞群体。MSCs还通过旁分泌效应刺激局部组织再生，诱导血管生成性、抗纤维化和重塑反应。MSCs可以大量从脐带（UC）中获取。在同种异体环境中使用的脐带间充质干细胞（UC-MSCs）在包括炎症性和免疫性疾病在内的多种疾病状况的临床试验中已证明其安全性和有效性。UC-MSCs已被证明可抑制肺部炎症和纤维化，并已在试点性、非对照临床试验中用于治疗重症COVID-19患者，这些试验报告了有前景的结果。我们机构处理的UC-MSCs已获得美国食品药品监督管理局（FDA）批准，用于阿尔茨海默病患者和1型糖尿病（T1D）患者的临床试验。我们假设UC-MSC也将对伴有细胞因子风暴和ARDS的COVID-19患者发挥有益的治疗作用。我们提议在患有ALI/ARDS的COVID-19患者中进行一项早期对照、随机临床试验。治疗组的受试者将接受两剂UC-MSC（100×10⁶个细胞）治疗。第一剂将在研究入组后24小时内输注。第二剂将在第一次输注后72±6小时给药。对照组的受试者将按照相同的时间安排接受载体输注（静脉输注补充有1%人血清白蛋白和70 U/kg普通肝素的 Dulbecco's 磷酸盐缓冲盐水 ）。在最初6天内每天对受试者进行评估，然后在入组后的第14、28、60和90天进行评估（有关时间窗口详细信息，请参见评估时间表）。安全性将通过随访期间的不良事件（AE）和严重不良事件（SAE）来确定。疗效将通过临床结果以及各种肺部、生化和免疫学测试来定义。当前研究的成功将为更大规模的对照、随机临床试验提供框架，并为满足这一紧迫但未得到满足的医疗需求加速可能的解决方案提供一种手段。拟议的早期临床试验将在迈阿密大学（UM）、迈阿密大学米勒医学院糖尿病研究所（DRI）、UHealth重症监护病房（ICU）以及临床转化研究站点（CTRS）的设施中进行，并在杰克逊纪念医院（JMH）开展。
