Amidst the scramble and panic-buying that some of us are experiencing, several treatments to combat this novel coronavirus (COVID-19) are underway. As of this writing, there are 66 clinical trials listed on ClinicalTrials.gov and of which, 7 studies involve the use of mesenchymal stromal/stem cells (MSCs).
Despite how recent these trials were initiated, things are progressing very quickly, so far one group led by Dr. Hu Min at Kunming University has reported promising results from one patient, a 65-year-old woman who recovered after given two shots of MSCs. This news was published in the South China Morning Post on March 2, and the full technical publication can be found here [1].
Sound promising? Wait, this was only one patient.
On March 13, an international team led by Dr. Kunlin Jun at The University of North Texas Health Science Center at Fort Worth reported their findings. In this study, they enrolled and treated 7 patients with MSCs, all of whom were discharged after 14 days. The primary claims of this study were “pulmonary function and symptoms of seven patients were significantly improved 2 days after MSC transplantation” and “MSC therapy can inhibit the overreaction of the immune system” [2].
While these early studies are showing some positive results, I am sure some of you must be wondering, can MSCs really help patients with COVID-19? And if so, how?
What do experts say?
Dr. Paul Knoepfler, a reputed figure in the stem cell community and author of the top stem cell blog (The Niche) has been following this development closely and published several posts (here, here and here) around this topic. As a skeptic, Paul’s primary concerns are: How effective would intravenous (IV) infusions of MSCs be and more importantly, what is the mode of action / mechanism of MSCs? With this in mind, I thought it might be useful to dig deeper into this topic and see what we know and what we do not.
Given the flood of information and news on COVID-19 these days, I think it is critical for us to stay objective and be critical about interpreting the results we see. The last thing we want is to see the rise of stem cell clinics taking advantage of the situation while everyone is panicking, as recently warned by ISSCR.
Understanding COVID-19
To understand why MSCs might be useful as a treatment, I thought we start with understanding how this infection works. What do we know about COVID-19? Recently, USA Today published an article providing some great visuals on how the coronavirus infection do to our body and here’s what we know so far:
- This is a respiratory virus that enters through the respiratory tract.
- The virus infects epithelial cells in the lining of the lungs and attacks the lungs.
- As the virus replicates, it causes respiratory problems like bronchitis and pneumonia, damaging alveolar cells and causing inflammation in the alveolar walls.
- Thickening of the walls in the alveolar lining chokes off oxygen and air exchange in our lungs, which ultimately affects and damage major organs.
- In more severe cases, though a small number, this can lead to acute respiratory distress syndrome (ARDS).
Primarily, the battle here is between the patient’s immune response and the virus. An over-reaction of the immune system inducing a cytokine storm can lead to multiple organ failure and eventually death.
Why MSCs?
Mesenchymal stromal/stem cells (MSCs) are well-known for the immuno-modulatory capabilities and have been used in clinical trials to treat various immune conditions such as Graft versus Host Disease (GvHD), irritable bowel disease (IBD) and not surprisingly inflammatory lung disease [3] and respiratory distress [4]. In fact, a local Bay Area UCSF resident and critical care specialist, Dr. Michael Matthay have been running and published several clinical trials using MSCs to treat acute respiratory distress syndrome (ARDS).
In this article [5], Dr. Matthay summarizes the therapeutic benefits of MSCs for ARDS based on his findings on a Phase 1 trial. More recently, Dr. Matthay also published his Phase 2a results [6] on Lancet Respiratory Medicine, showing no adverse events in 60 patients enrolled, demonstrating safety in critically ill patients with ARDS.
Dr. Matthay is currently running a Phase 2b multi-center clinical trial evaluating safety and efficacy of a single dose of allogeneic bone marrow derived MSCs at 10 million cells/kg for ARDS.
How can MSCs treat COVID-19?
While we may not know or have any answers yet as to how MSCs can be used to treat COVID-19, it may be useful to gain insights on what we have observed or learned from ARDS. In understanding ARDS and its pathophysiology, Dr. Carolyn Calfee from UCSF explains what happens to our alveolar during acute lung injury:
- The alveolus is filled with pink, pulmonary edema fluid which is filled with inflammatory cells & cytokines.
- The lining of aveolar is necrotic and denuded in some areas.
Watch the full explanation in this youTube video.
Noted here, some similarities observed with COVID-19 include inflammation and damage to epithelial cells on the alveolar lining.
Further, Dr. Matthay explains their rationale on how or why MSCs can work to treat ARDS. Key highlights of this youTube video include:
- MSCs have anti-inflammatory properties and restore endothelial & epithelial barrier integrity
- MSCs can enhance alveolar & lung edema fluid clearance
- MSCs have anti-microbial properties and anti-apoptotic effects.
A primary mechanism observed thus far is the paracrine effects of MSCs in reducing lung injury and enhancing lung repair. For a more in-depth insight into the mechanisms of potential therapeutic effects of MSCs on ARDS and sepsis, read Dr. Matthay’s 2014 Lancet paper [7].
Best case scenario – what next?
In the best case scenario, let’s say we accumulated enough data to demonstrate both safety and efficacy of MSCs to treat COVID-19, and FDA fast-tracks its approval for commercial use. How can we make this novel therapy available to treat 10,000 patients in the shortest time possible? Current confirmed cases to date, as of March 15, is already 165,687 with 75,620 recovered and 6065 deaths so far.
Fortunately, as MSC manufacturing experts, our team at RoosterBio is already prepared to tackle this problem. Assuming that each patient would require at least 300 millions cells per dose, we would need to manufacture an estimate of 6.4 trillion cells (including product loss and QC testing) as our experts calculated. If we were using current conventional 2D cultures with 10-layer flasks, this would require 640 manufacturing lots! That’s a lot of work guys!!!
Do we have an alternative? Of course, read this RoosterBio blog to learn more.
In concluding, despite the chaos, stress, and fears that COVID-19 is putting on all of us, individuals and businesses alike, I think it is important to stay focused on finding solutions and working together as a community to fight this pandemic. Each and every one of us can contribute and help each other, and the greater community by staying focused and being objective. My first step is by sharing valuable information and insights around the solutions focused to tackle this pandemic, and educating the general public about what they should know when it comes cell therapy.
References
[1] Liang, Bing, et al., Clinical remission of a critically ill COVID-19 patient treated by umbilical cord mesenchymal stem cells. ChinaXiv, 2020. http://chinaxiv.org/abs/202002.00084
[2] Leng, Zikuan, et al., Transplantation of ACE2- mesenchymal stem cells improves the outcome of patients with COVID-19 Pneumonia. Aging and Disease, 2020. 11(2): p. 216-228. https://doi.org/10.14336/AD.2020.0228
[3] Harrell, C. Randall, et al., Mesenchymal stem cell-based therapy of inflammatory lung diseases: current understanding and future perspectives. Stem Cells Int, 2019. Article ID 4236973. https://doi.org/10.1155/2019/4236973
[4] Hayes, Mairead et al., Mesenchymal stem cell therapy for acute respiratory distress syndrome: A light at the end of the tunnel? Anesthesiology, 2016. 122(2): p. 238-240. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301977/
[5] Matthay, Michael A. Therapeutic potential of mesenchymal stromal cells for acute respiratory distress syndrome. Ann Am Thorac Soc, 2015. 12(Suppl 1): p. S54-S57. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301977/
[6] Matthay, MA. Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomized phase 2a safety trial. Lancet Respir Med, 2019. 7(2): p.154-162. https://www.ncbi.nlm.nih.gov/pubmed/30455077
[7] Walter J, Ware LB, Matthay MA, Mesenchymal stem cells: mechanisms of potential therapeutic benefit in ARDS and sepsis. Lancet Respir Med, 2014. 2(12): p.1016-26. https://www.ncbi.nlm.nih.gov/pubmed/25465643