Reducing mortality and morbidity in patients with severe COVID-19 disease by advancing ongoing trials of Mesenchymal Stromal (stem) Cell (MSC) therapy — Achieving global consensus and visibility for cellular host-directed therapies

Abstract

As of May 17th 2020, the novel coronavirus disease 2019 (COVID-19) pandemic has caused 307,395 deaths worldwide, out of 3,917,366 cases reported to the World Health Organization. No specific treatments for reducing mortality or morbidity are yet available. Deaths from COVID-19 will continue to rise globally until effective and appropriate treatments and/or vaccines are found. In search of effective treatments, the global medical, scientific, pharma and funding communities have rapidly initiated over 500 COVID-19 clinical trials on a range of antiviral drug regimens and repurposed drugs in various combinations. A paradigm shift is underway from the current focus of drug development targeting the pathogen, to advancing cellular Host-Directed Therapies (HDTs) for tackling the aberrant host immune and inflammatory responses which underlie the pathogenesis of SARS-CoV-2 and high COVID-19 mortality rates. We focus this editorial specifically on the background to, and the rationale for, the use and evaluation of mesenchymal stromal (Stem) cells (MSCs) in treatment trials of patients with severe COVID-19 disease. Currently, the ClinicalTrials.gov and the WHO Clinical Trials Registry Platform (WHO ICTRP) report a combined 28 trials exploring the potential of MSCs or their products for treatment of COVID-19. MSCs should also be trialed for treatment of other circulating WHO priority Blueprint pathogens such as MERS-CoV which causes upto 34% mortality rates. It's about time funding agencies invested more into development MSCs per se, and also for a range of other HDTs, in combination with other therapeutic interventions. MSC therapy could turn out to be an important contribution to bringing an end to the high COVID-19 death rates and preventing long-term functional disability in those who survive disease.

Human umbilical cord-derived mesenchymal stem cell therapy in patients with COVID-19: a phase 1 clinical trial

“…MSCs derived from different tissues, including human bone marrow, umbilical cord tissue, adipose tissue, lung tissue, dental pulp, and placenta, 7 have been used in humans, without serious adverse events to treat corticosteroid-resistant graft-versus-host disease, multiple sclerosis, heart failure, acute respiratory distress syndrome (ARDS), and other indications. 11 – 14 However, their use and safety profile in patients with COVID-19 needs to be determined in light of the multi-system nature of disease associated coagulopathy. Therefore, we performed a parallel assigned, controlled, non-randomized, phase 1 clinical trial to evaluate the safety of human umbilical cord-derived mesenchymal stem cells infusions in the treatment of patients with moderate and severe COVID-19 during the early phase of the COVID-19 pandemic since 27 January 2020.…”

Mesenchymal Stromal Cells in Viral Infections: Implications for COVID-19

“…Nowadays, the COVID-19 pandemic represents a public health emergency and has prompted an urgent need for novel or alternative therapies [5,103,105,[123][124][125][126][127]. Almost every patient with COVID-19 presents with lung involvement, whereas severe complications, such as ARDS, are only observed in a subgroup of severe patients.…”

“…In addition, intravenously infused MSCs become trapped in the lung. In the case of COVID-19, this fact may be beneficial as the lung is the primary organ affected by SARS-CoV-2 [5,103,105,[123][124][125][126][127].…”

“…Moreover, several challenges still have to be addressed, especially MSC dosing and timing of administration, since an exacerbated immunosuppression may have the reverse effect [5,103,105,[123][124][125][126][127]. The MSC-based clinical trials should be carefully designed (randomized; placebocontrolled; large patient cohorts) to ensure that the results will be effective, accurate, trustworthy and significant.…”

The rising role of mesenchymal stem cells in the treatment of COVID-19 infections

“…MSCs in the treatment of patients with COVID-19 having ALI and ARDS [73][74][75]. In the era of COVID-19 pandemic, several groups of scientists from all over the world have recommended the use of MSCs in the treatment of severe COVID-19 infections as MSCs and their secretomes have the following bene icial effects: suppression of viral replication; enhancement of the generation of regulatory T-cells that are suppressed by COVID-19; shifting the phenotype of antigen presenting cells including DCs, B-lymphocytes, and macrophages; modulation of the proliferation and activation of naïve and effector T-cells, NKCs, and mononuclear cells; prevention of the formation of NETs; inhibition of the cytokine storm induced by COVID-19; the antiviral, antibacterial, and analgesic effects of MSC-secretomes; reduction in pulmonary edema associated with ARDS in COVID-19; entrapment of IV infused MSCs in the lungs; enhancement of tissue regeneration and promotion of endogenous repair and healing in ALI; as well as safety and ef icacy of MSCs and their products provided good manufacturing practice guidelines and quality control measures are taken into consideration [8,13,34,44,52,54,73,[75][76][77][78][79][80][81][82][83][84][85][86].…”