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Exploring the Utility of Stem Cell Therapy for COVID-19

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Whilst the production of a safe and effective vaccine for SARS-CoV-2 is the ultimate aim of the COVID-19 response, research is also underway to develop novel treatments that could help infected patients in the meantime. One growing area of interest is the use of stem cell therapy: the results of two studies conducted in China indicate that its use seems to be particularly efficient in the case of severely ill patients, and the US Food and Drug Administration recently authorized compassionate use of mesenchymal stem cell intravenous infusions in patients with a very dismal prognosis.

To learn more about the science behind stem cell therapies and 
how such a therapy would be produced and administered to COVID-19 patients, Technology Networks recently spoke with Giuseppe Mucci, CEO, Bioscience Institute.

Anna Macdonald (AM): Can you explain some of the immunomodulatory effects stem cells can have and why this is particularly significant for COVID-19 patients?

Giuseppe Mucci (GM): 
Mesenchymal Stem Cells (MSCs) are multipotent cells found in various locations in the body including adipose tissue, bone marrow, placenta and umbilical cord. These cells can be easily harvested, isolated, cultured and used in cell-based therapy, from basic research to clinical trials. Safety and effectiveness have been clearly documented in many clinical trials, especially in the immune-mediated inflammatory diseases, such as graft versus-host disease and systemic lupus erythematosus. MSCs play a positive role mainly in two ways, namely immunomodulatory effects and differentiation abilities. MSCs can secrete many types of cytokines by paracrine secretion or make direct interactions with immune cells, leading to immunomodulation.

The immunomodulation activity of mesenchymal stem cells was further confirmed in an interesting two-year-long clinical trial carried out by the University of Miami, where the researchers used these cells for the treatment of frailty. We also know that the immunomodulatory effects of MSCs are triggered further by the activation of toll-like receptors in MSCs, which is stimulated by pathogen-associated molecules such as lipopolysaccharides or RNA from a virus, such as SARS-CoV-2.

Several reports demonstrated that the first step of COVID-19 pathogenesis is that the virus specifically recognizes, infects and destroys cells via two specific molecules, ACE2 and TMPRSS2. Unfortunately, the ACE2 receptor is widely distributed on the surface of human cells, especially lung alveolar cells, capillary endothelium and on some cardiac cells.

The immune system and its regenerative ability is compromised by age and, unfortunately, as we know very well, the elderly are strongly hit by this disease. Studies of the outbreak so far show that eight in 10 patients who are struck down with a severe case of coronavirus will be over 65. People under the age of 50 are supposed to have healthier immune systems than those who are older. This means their bodies should recognize an alien agent, such as the novel coronavirus, fairly quickly after it enters their cells and start producing antibodies to fight it.

Before the virus has had time to cause any of the serious breathing problems and nasty pneumonias in the lungs, their immune system should have fought it off, and they should be well on the road to recovery, suffering only a fever, dry cough and fatigue.

However, it is the youthful immune system that may become the problem in some subjects. As the immune system recognizes and prepares to attack the virus, small unknown and otherwise harmless genetic or environmental factors can cause the immune system to go into overdrive.

Inflammatory cells can release an excessive quantity of cytokines, which should help produce a hostile environment for the infection and sets off a chain event called a "cytokine storm". This is an over-reaction on the part of the immune system. This means that the immune system is unable to turn itself off once it has generated enough of a defence against the virus. Inflammation caused by the immune system continues at an unchecked and accelerated rate and floods the lungs with fluid, making it difficult to breathe. A prolonged cytokine storm will eventually shut down breathing completely.

Mesenchymal stem cells used in patients that have been affected by the cytokine storm may fine balance the immune system in order to stop the overreaction, without switching it  off completely, so that the immune system can continue to fight the infection.

In elderly patients, MSCs may support the immune response as already proved by the Florida University trial and support the healing process absolutely necessary after the damage generated by the virus.

Molly Campbell (MC): The FDA has approved compassionate use of MSCs, specifically allogeneic (from a donor) stem cells. For our readers that may be unfamiliar with the approval processes, what does this mean?

 Compassionate drug use refers to the use of a new, unapproved drug to treat a seriously ill patient when no other treatments are available. To date, there is no specific cure for COVID-19. Clinical management of these patients currently includes prevention or control of the infection and supportive care, including supplemental oxygen and mechanical ventilation support when needed.

MSCs are recognized by the FDA as well as the European Medicines Agency (EMA) as a therapy that has already proven to be safe and in several cases effective in a number of American and European trials. Considering this and the early Chinese study reports regarding the efficacy of MSCs in the treatment of severe COVID-19 patients, FDA has granted compassionate  use approval.

We can use MSCs obtained from your own tissue (autologous use) or from another individual's tissue (allogenic use). For several reasons, autologous use is the elective way, but considering that the production of the cells can take a considerable amount of time and we are currently in an emergency situation, if the patient has not already banked MSCs the only option is allogenic use. These cells can, in some way, evade the normal rules of self and not self that usually regulate the organ and tissue donation, and this allows allogenic use.

MC: Please can you tell us more about the results of the studies that have been conducted in China?

Two recent studies have taken place in China, and both studies reveal remarkable reversal of symptoms even in severe-critical conditions.  The scientists have not only identified a novel therapeutic strategy, but also the existence of natural mechanisms able to counteract acute inflammatory pneumonia.

One study is a case report of a critically ill COVID-19 patient on a ventilator who had progressed despite intensive therapy, with markers showing evidence of liver injury. This patient was treated with allogeneic MSCs using three intravenous infusions of 5x107 MSCs, three days apart. Within four days of the patient's first cell infusion, she was off the ventilator and able to walk. All measured parameters, including circulating T cell counts, returned towards normal levels.  No obvious side effects were observed.

The second study, the Beijing YouAn Hospital study, was a pilot clinical trial to assess whether MSC transplantation could improve the outcome of seven enrolled patients with clinical COVID-19 pneumonia, with one case determined as critically severe, four severe, and two non-severe. Before transplantation, all individuals had high fever, shortness of breath and low oxygen saturation. Treatment included a single intravenous dose of clinical grade MSCs, 1x106 cells per kg of weight. Detailed follow-up over 14 days post-transplantation showed no adverse effects, and within two days all patients had significantly improved pulmonary function, including the one severe COVID-19 pneumonia case, who was well enough for discharge by day 10. Overall, after treatment, the immune system in a “cytokine storm”-like condition returned to a normal status. 

MC: Please can you talk us through how a stem cell therapy would be produced and administered to COVID-19 patients? 

 MSCs can be isolated from several sources including adipose tissue, bone marrow, placenta, cord blood tissue etc. The harvested tissue is transferred to a Good Manufacturing Practice compliant cell factory where the cells of interest are isolated. The number of cells that can be isolated from the tissues is very low and not sufficient for therapeutic protocols, which require hundreds of millions of cells. That is why we need to expand them in a culturing process that normally requires two to four weeks.  Once the cells are ready, the patient will receive the cell-based drug as intravenous infusions.

MC: Does data exist on which time-point post-infection the therapy would produce the highest efficacy?

 At the moment, MSCs based therapy is used as emergency protocol mainly for the control of the cytokine storm when the patient is in a severe condition. However, as several studies have already shown, these cells can be used as a preventative treatment especially in the elderly patient.

MC: Are there safety implications to developing a stem cell therapy for treating COVID-19?

To claim that the development of a novel therapy, regardless of what it is, is free of risk is not scientifically and ethically correct. The data available at the moment has not reported side effects linked with the use of MSCs when the cells are produced by reliable groups with strong and validated quality systems.

Giuseppe Mucci, was speaking to Molly Campbell and Anna MacDonald, Science Writers, Technology Networks.