Who else out there has fallen into the Coronavirus Media Hole and can’t get out? It’s become this daily, masochistic ritual that I read all of the reports of new cases, new hospitalizations, new shortages of supplies, and worsening forecasts for the near future. My family and I have watched all of the pandemic movies (feel free to report me to Child Protective Services) and have now moved on to war movies because they make us feel better about our current state of affairs.
But, despite all of the above, I remain hopeful. I’m hopeful because as a former ER doctor who left a piece of my heart in the emergency department when I walked out 7 years ago, I know that we have the very best people on the ground dealing with this dumb virus.
I’m hopeful because I know the smartest scientists from all over the world are working on vaccines and drug therapy to put Mr Covid 19 in his place.
And, I’m hopeful because I think regenerative medicine has the potential to make a real difference in how this pandemic plays out and how we react to future viruses-gone-wild scenarios.
The Beijing Study: Covid 19 + Umbilical MSC’s
In Jan-Feb, 2020, as part of a study protocol, a Beijing hospital treated 7 confirmed Covid 19 patients with intravenous umbilical Mesenchymal Stem Cells (uMSCs). They also treated 3 patients with placebo. Of the three placebo patients, one died, one became Severe, and one developed ARDS. All of the 7 MSC-treated patients recovered and were discharged within 14 days.
All of the patients in this study had respiratory compromise with low oxygen saturations, difficulty breathing and weakness before treatment. The MSC- treated group included Common, Severe and Critical patients. Shockingly, within 2-4 days, all of the treated patients were symptom-free with blood oxygen levels >95%. The Critical patient, who was showing signs of severe liver and cardiac damage initially, normalized his blood markers within the same 2-4 days. That same patient, who had also developed severe Acute Respiratory Distress Syndrome (ARDS) and had ground-glass white-out on his chest CT, saw almost complete resolution of this difficult-to-treat inflammatory process within 2 weeks.
Oh, and this entire stem cell treatment, which caused no side effects, was performed through a simple IV over a single session that took a total of 40 minutes.
MSC’s – The body’s mobile pharmacy
Mesenchymal stem cells (MSC’s) are a type of stem cell (or at least progenitor cell, depending on who you talk to) that exist in various tissues in our bodies. Also known as “medicinal signaling cells” these cells are capable of replication, differentiation and signaling. For purposes of discussion around coronavirus the signaling function of these cells may be the most important attribute.
MSC’s are known to have anti-inflammatory, anti-bacterial, antiviral and immunomodulatory effects. All of these things could come in handy when talking about treating Covid 19 patients.
Covid 19 is caused by a virus called SARS CoV2, which is similar to the virus that causes both SARS and MERS. SARS CoV2 (hereto known as The Virus) finds its way into cells by binding to a specific receptor called the ACE2 receptor (Angiotensin I Converting Enzyme 2), which is found on many cells in our bodies and is normally useful in helping us maintain our blood pressure. So,The Virus binds to ACE2 by its spike proteins and wiggles its way into our unsuspecting cells. Cells in our alveoli (lungs) and capillaries seem to be especially susceptible to invasion.
Once our immune system realizes that it’s been attacked, it launches an immune response in an attempt to clear the virus. Sometimes, however, our immune system over-shoots and we get too many inflammatory cytokines on the scene. This “cytokine storm” is being blamed for many of the severe lung problems seen in Covid 19 patients. Inflammatory cytokines cause damage to the cells in the lungs, resulting in extra fluid accumulating (edema), which causes impaired air exchange. Eventually, this can cause ARDS, which is an extremely difficult-to-treat diffuse lung disease.
MSC’s can reduce inflammation and modify immune responses
It’s the ability of MSC’s to reduce inflammation and modulate the way immune cells behave that makes them a potentially effective treatment in these patients with Covid 19 and ARDS. In fact, in the Beijing study above, patients who were treated with umbilical MSC’s saw drastic reductions in pro-inflammatory cytokine levels (such as TNF-alpha and IL-10). General markers of inflammation, such as CRP, also improved within days of MSC therapy.
These immunomodulatory properties of MSC’s are well known and have been demonstrated in a number of diseases, such as Graft-vs-Host Disease (GVHD) and Systemic Lupus Erythematosus (SLE). Many researchers have studied MSC’s delivered intravenously to treat other autoimmune diseases as well, including Multiple Sclerosis and Rheumatoid Arthritis. In all of these cases, the ability of the transplanted MSC to modify how the host’s immune system is responding to an injury (real or perceived) is a key reason these therapies seem to be helpful.
ARDS (Acute Respiratory Distress Syndrome) is classically extremely difficult to treat. Prior to the recent Covid 19 outbreak, ARDS affected about 20,000 Americans a year and killed 30-50% of those affected. Causes of pre-Covid 19 ARDS included infection and trauma, among other things. Without good available treatments for ARDS, these patients are generally managed with “supportive care”, which means they are put on a ventilator and the ICU team tries to keep them alive and oxygenating long enough for their bodies’ immune systems to calm the F down long enough for the lungs to repair themselves.
MSC’s given intravenously, such as in the Beijing study, will go first to the lungs, where most of them may get trapped, resulting in their potential benefit in preventing/treating this cytokine storm seen in ARDS.
Exosomes and Coronavirus
Exosomes are tiny extracellular vesicles that are released by MSC’s into the environment around them. It was once thought that these tiny little bubbles (as I like to think of them) just contained cellular debris. However, it’s now recognized that exosomes are mediators of intercellular communication. When a stem cell wishes to communicate with nearby cells, one of the key ways it does that is by releasing exosomes, which contain bundles of information such as micro-RNA, proteins and lipids. The exosomes get taken in by nearby host cells, which is where the fun starts.
Exosomes can transfer their information to the host cell, thus affecting how the host cell behaves. For example, micro RNA from the exosome can change how the host cell produces proteins and responds to stimuli in the environment. It’s like the exosome is transfering over a new blueprint on how to be an up-standing, healthy cell, which changes how that host cell acts. Exosomes have been shown to transfer mitochondria to host cells as well, which may be used as an energy source for diseased or fatigued cells. And, like MSC’s, exosomes have been shown to be able to decrease inflammation and modulate how immune cells function.
There is a study going on right now in China looking at giving aerosolized MSC-Exosomes for Covid 19 patients with pneumonia. Preclinical studies support that these exosomes might be very helpful in treating ARDS in these patients.
A meta-analysis of pre-clinical (animal studies and in vitro studies) conducted in 2019 looked at evidence supporting the use of extracellular vesicles (EV’s), such as exosomes, in ARDS. Intra-tracheal EV installation improved symptoms and survival in animal models with acute lung injury and ARDS. So far, these therapies appear safe as well as effective. Like MSC’s, these exosomes were shown to decrease pro-inflammatory signaling and increase anti-inflammatory mediators, but they did so without using actual cells, which could make these therapies easier for mass production.
Finally, studies point to exosomes from MSC’s as being able to inhibit replication of certain viruses, which could be good news for this coronavirus pandemic. In an in vitro Hepatitis C study, miRNA from exosomes suppressed viral RNA translation to protein, resulting in suppressed viral replication. In this study, exosomes worked synergistically with drug therapy to fight Hepatitis C . In a pig model of the influenza virus, intra-tracheal administration of EV’s significantly reduced viral shedding in nasal swabs and viral replication in the lungs.
All of the above, taken together, is encouraging. Lab and animal data point to MSC’s and MSC-Exos as having antiviral and anti-inflammatory activity and animal and human studies have pointed to MSC’s as being helpful for ARDS. Multiple human studies have shown MSC’s and Exos can modulate immune responses, helping to tamp-down overactive immune reactions in a variety of disease conditions. A small Beijing study on humans with Covid 19 pneumonia points to the administration of a single dose of IV MSC’s as contributing to multi-organ system recovery and, ultimately, may have helped 14 patients walk out of the hospital on their own two feet.
The near future:
Obviously, we need more data, but given the apparent safety of these therapies, I for one want to go on record saying that I’m a fan and that we need to fast-track these therapies.
Luckily, several companies are looking at modifying their stem cell products to treat Covid 19 patients. For example, Athersys and Mesoblast both have stem cell products that may be helpful in the ARDS component of Covid 19. Athersys’s Multistem, which uses bone marrow derived stem cells, has shown encouraging results in treating very sick people with ARDS and had no serious side effects through one year follow up. Mesoblast’s Remestemcel-L was developed for treating graft vs host disease (GVHD) but also showed promise in treating chronic obstructive pulmonary disease (COPD), which shares many of the same elevated inflammatory markers as ARDS. Kimera Labs, makers of umbilical MSC-Exos, is also working hard to contribute to healing during this pandemic. The list goes on, which is awesome.
I’d like to end this with a plea to the Powers That Be that we (as a country) pull our heads out of the sometimes-deep-and-deadly-bureaucratic-quick-sand to make these types of regenerative therapies available to actual people (not just petri dishes and lab rats) as soon as humanly possible.
And, if I happen to end up in the ICU with a tube in my lungs and ground glass densities on my CT scan, I hope someone will find a way to sneak a large dose of MSCs into my scrawny veins (and maybe a few vials of exosomes down my endotracheal tube) before everyone throws up their hands and marks me down as one more Covid 19 fatality that we simply couldn’t do anything to prevent.