COVID-19, DIABETES, AND MESENCHYMAL STEM CELLS: GROUNDBREAKING FINDINGS BRING NEW HOPE
by Giacomo Lanzoni, PhD
COVID-19: are we out of the woods?
Since the end of 2019, COVID-19 has turned the world upside down. Even today, with vaccines and novel treatments, this disease poses a huge threat to global public health. Two years into the pandemic, this disease continues to wreak havoc because of its high rate of infection, rapid spread during waves, severe morbidity and mortality (Figure 1).
Figure 1) Daily new confirmed COVID-19 deaths, 7 days rolling average (source: Our World in Data)
Right now, hospitals in Japan and Hong Kong are overwhelmed by the onslaught of a new wave of infections, which unfortunately is leading to grim new records of cases and deaths there (Figure 2, 3).
Figure 2) Confirmed COVID-19 deaths in Japan (source: Our World in Data)
Figure 3) Confirmed COVID-19 deaths in Hong Kong (source: Our World in Data)
Vaccination campaigns have helped enormously in limiting morbidity and mortality due to COVID-19, but even with 4 billion fully vaccinated individuals worldwide, new deaths from COVID-19 remain high (Figure 4).
Figure 4) COVID-19 vaccine doses and confirmed deaths per million, worldwide (source: Our World in Data)
Globally, over these two years, 5.9 million COVID-19 deaths have been officially reported. Analyses of excess mortality indicate that the true number of COVID-19-related deaths is painfully higher, between two and four times that figure (1). Excess mortality captures deaths from all causes and gives us a clear picture of the severity of the pandemic. This metric involves comparing all deaths recorded with those expected to occur, based on data from previous years.
Excess mortality in the United States remains very high compared to previous years (Figure 5).
Figure 5) Excess mortality in the United States (source: Our World in Data)
COVID-19 spreads in waves, primarily connected to newly emerging variants of the SARS-CoV-2 virus. During the waves of infections, hospitals can become overwhelmed and even treatment of other disease, beside COVID-19, becomes problematic. Intensive Care Units (ICU) have seen rapid influx of patients during the worse waves of COVID-19 infection, with the last peak occurring just one month ago due to the Omicron variant (Figure 6).
Figure 6) Number of COVID-19 patients in intensive care (ICU) (source: Our World in Data)
Just a few weeks ago, Denmark lifted all restrictions and declared that COVID-19 no longer poses a threat to society. Since then, COVID-19 deaths there have increased to record levels (Figure 7) and a new SARS-CoV-2 variant termed BA.2 has become dominant over Omicron
Figure 7) Confirmed COVID-19 deaths in Denmark (source: Our World in Data)
So are we out of the woods? It is hard to say, but the current situation in Denmark, Japan and Hong Kong suggests that we are not.
COVID-19 and Diabetes
One thing is certain: SARS-CoV-2 is dangerous, so we need prevention and better treatments. This is crucially important for patients with diabetes.
Because of their underlying disease, people with diabetes are more likely to have complications from COVID-19 (2). In patients with diabetes the increased levels of glucose in the blood, the increased level of inflammation, and the problems at the level of beta cells all facilitate the emergence of symptoms that are more severe. Importantly, a good management of diabetes enables to lowers these risks.
Not only COVID-19 affects more severely those subjects with diabetes, but it could even cause diabetes in those without.
A study has reported that 14% of people hospitalized due to COVID-19 developed new onset of diabetes (3). SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas, including insulin producing beta cells (4). Even in those with mild COVID-19 symptoms, SARS‑CoV‑2 infection can lead to a broad autoantibody response (5). Early during the pandemic, a substantial increase in new onset type 1 diabetes was observed, corresponding to an increase of 80% over what used to be observed in a typical year (6). Although this diabetes appeared to be transient in many cases, it did persist in a subset of patients. Notably, this topic remains a matter of debate (7, 8), but it is possible that COVID-19 could trigger autoimmunity and type 1 diabetes.
We still need better treatments for severe COVID-19
We now have vaccines and new agents that are efficacious in the early and intermediate phases of COVID-19 disease progression, but we still need better treatments for severe COVID-19.
In its severe form, COVID-19 is characterized by an extremely elevated inflammation, termed “cytokine storm”, and acute respiratory distress syndrome (COVID-19 ARDS). Mortality in patients that develop such severe disease is dramatically high: it was reported to be 52.4% (9). Hence, there is an urgent need to develop strategies that can lower the extreme risks of COVID-19 ARDS.
Enters our hero: Mesenchymal Stem Cells (MSC)
At the DRI, we have been studying Mesenchymal Stem Cells and their immunomodulatory properties for more than a decade. These cells can function as potent inhibitors of inflammation, can modulate immunity, and can stimulate Regulatory T cells (Tregs). Intense studies are ongoing at our Institute to use these cells to fend off autoimmunity in type 1 diabetes and to limit progression of diabetes complication. In a recent groundbreaking clinical study, treatment with these cells was found to be associated with the abatement of chronic complications of type 1 diabetes over an 8 years follow-up (10). Moreover, these cells have shown remarkable properties in facilitating allogeneic islet transplantation (11). Furthermore, these cells can stimulate tissue regeneration and revascularization. Lastly, MSC can inhibit fibrosis.
In 2019 and early 2020, we were developing methods to grow these cells to scale, in a clinical-grade production at the DRI cGMP facility, in view of an FDA-authorized clinical trial for type 1 diabetes.
When COVID-19 erupted, in the spring of 2020, we had clinical-grade cells ready to transplant and we had a strong gut feeling that these cells could have helped counteract the extreme inflammation in patients with COVID-19 ARDS.
Umbilical Cord-derived Mesenchymal Stem Cells (UC-MSC) for COVID-19 ARDS
In the early months of the COVID-19 pandemic, we worked feverishly to design and conduct a clinical trial that could provide meaningful safety data on Umbilical Cord-derived Mesenchymal Stem Cells (UC-MSC) treatment for COVID-19 ARDS. The results of this trial went above and beyond our expectations, demonstrating safety, bringing unprecedented observations of efficacy and indicating a probable mechanism of effect of these cells in patients.
The trial also enabled us to scale up production of the cells at our cGMP facility, and the FDA has recently authorized us to proceed with a larger Phase 3 trial. Our findings had a sizable impact, at the global scale, and continue to resonate in the field of cell therapy.
But let us explain more in depth what we did, and what we observed.
As stated above, we were growing UC-MSC cells in a clinical-grade production at the DRI cGMP facility. With the leadership of Dr. Ricordi, we worked in close coordination with Intensive Care Units in the Miami area, at University of Miami`s UHealth, Jackson Memorial Hospital, and Jackson South Medical Center.
Our team at the Diabetes Research Institute led the study and collaborated in the design with preeminent investigators at Case Western Reserve University (US), University of Arizona (US), and Hainan Medical University (China). We performed a double-blind randomized controlled trial of UC-MSC for COVID-19 ARDS (12). ‘Double-blind’ means that neither the patient nor the researchers/doctors know whether the patient is receiving the investigational treatment or control. ‘Randomization’ is the process by which participants are assigned by chance to either investigational treatment group or control group. ‘Controlled’, or ‘placebo-controlled’ trial is a trial in which one group gets the active investigational treatment, the other group gets a placebo. A trial with all of these characteristics is solid, and thus yields a high level of evidence. Our trial was one of the few in the field bringing such high level of evidence (as commented in 13).
These are the key take-home messages from our trial (see Figures 8, 9):
- In our trial, we observed that two intravenous infusions of UC‐MSC, at a dose of 100 million cells per infusion, given 72 hours apart, are safe in COVID‐19 patients with ARDS.
- Our trial demonstrated fewer serious adverse events (SAE) in the UC‐MSC treatment group compared to the control group (Figure 8).
- UC‐MSC treatment was associated with a significant decrease in a set of inflammatory cytokines involved in the COVID‐19 “cytokine storm” (Figure 9).
- UC‐MSC treatment was associated with significantly improved patient survival and time to recovery (Figure 8).
Figure 8)‘Kaplan‐Meier’ curves at 31 days after the first infusion: A) Survival. B) Serious Adverse Event (SAE)-free survival, C) Time to recovery . At 31 days after the first infusion (patient survival was 91% in the UC‐MSC treatment group versus 42% in the control group.
Figure 9) In our trial in COVID-19, UC-MSC treatment was associated with a rapid and substantial decrease in mediators of inflammation.
This study yielded remarkable evidence of safety and efficacy of UC-MSC treatment in COVID-19 ARDS, strongly supporting further investigation in a larger trial designed to estimate and establish efficacy. The FDA has recently authorized us to proceed with a Phase 3 trial.
Even if our trial had enrolled ‘just’ 24 patients (this trial was ‘powered for safety’, which means ‘designed to provide clinically meaningful data on safety’), a strong efficacy signal was detected, indicating that UC-MSC could really have a profound positive effect.
In simple terms, our findings of UC-MSC efficacy in COVID-19 ARDS are mind-blowing.
UC-MSC treatment: exciting implications for patients with Diabetes!
What does this trial mean for patients with Diabetes? What does it mean for autoimmune Type 1 Diabetes, and for those with diabetic complications?
It means a lot.
First of all, patients with diabetes suffer more frequently from severe forms of COVID-19. In fact, 11 patients out of 24 enrolled in our trial also had diabetes. Strikingly, 100% of diabetic patients who received UC-MSC treatment recovered (5 out of 5), whereas only 33% of diabetic patients who received control recovered (2 out of 6). These observations strongly suggests a remarkable effect in patients with diabetes and COVID-19 ARDS.
Moreover, our trial demonstrated that UC-MSC work as we were hoping they would: as potent immunomodulators, inhibiting proinflammatory pathways.
So not only UC-MSC could become a tool in our armamentarium to fight COVID-19, but they could also be efficacious in our battle against autoimmune diabetes and inflammation.
Among the numerous inflammatory cytokines that are inhibited by UC-MSC, TNF alpha and TNF beta are crucial, because they function as master regulators of inflammation. We believe we may have found the molecular mechanism by which UC-MSC inhibit TNF: by increasing soluble TNF receptor 2 (sTNFR2, Figure 11), a molecule that sequesters TNF and blocks its proinflammatory effect (14).
Figure 10) In our trial in COVID-19, UC-MSC treatment was associated with an increase in soluble TNF Receptor 2 (sTNFR2) and a decrease in TNF alpha and TNF beta at day 6.
Inhibition of TNF is a core goal for the treatment of Type 1 Diabetes. It turns out that agents that inhibit TNF, such as the antibody Golimumab, can inhibit progression of autoimmune T1D – as shown in a recent clinical trial (15). We have hypothesized that UC-MSC treatment could inhibit T1D autoimmunity by inhibiting the TNF pathway of inflammation.
The fact that UC-MSC are immunomodulatory and impart an anti-inflammatory effect is also extremely relevant for diabetic patients suffering from complications. Diabetic Nephropathy is a prime example: it is one of the most problematic complications of diabetes, with a major inflammatory component. We hypothesized that UC-MSC could help lower inflammation and inhibit progression of Diabetic Nephropathy, supporting kidney function. Initial observations in the first patient with T1D and Diabetic Nephropathy appear very promising, but a clinical trial will be required to bring robust evidence.
The trial of UC-MSC treatment for COVID-19 also enabled us to scale up dramatically the production of these cells at the DRI cGMP facility, and to develop new methods to characterize the potency of these cells. As a result, our team at the DRI is now well positioned to start clinical testing of UC-MSC in the context of T1D and complications. We have already received authorization by the FDA for the clinical testing of UC-MSC in these contexts.
We believe that our findings in COVID-19 ARDS bring new hope for patients with diabetes.
These advancements were made possible by substantial support from the Diabetes Research Institute Foundation (DRIF), The Cure Alliance and the North America`s Building Trades Unions (NABTU). Our team at the Diabetes Research Institute is thrilled to bring this investigational cell therapy closer to fruition in Diabetes and its complications. In our view, these findings mark a major step towards a Cure.
Article written by:
Giacomo Lanzoni, PhD
Research Assistant Professor
Diabetes Research Institute
University of Miami
1) Adam D. The pandemic’s true death toll: millions more than official counts
Nature, News feature, 18 January 2022 https://www.nature.com/articles/d41586-022-00104-8#:~:text=On%201%20November%2C%20the%20global,figure%20is%20a%20significant%20underestimate.
2) Barron E et al. Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: a whole-population study doi: 10.1016/S2213-8587(20)30272-2. Epub 2020 Aug 13. PMID: 32798472 PMCID: PMC7426088 DOI: 10.1016/S2213-8587(20)30272-2
3) Sathish T et al. Proportion of newly diagnosed diabetes in COVID-19 patients: A systematic review and meta-analysis
Diabetes Obes Metab. 2020 Nov 27;10.1111/dom.14269. doi: 10.1111/dom.14269. PMID: 33245182 PMCID: PMC7753574 DOI: 10.1111/dom.14269
4) Müller JA et al. SARS-CoV-2 infects and replicates in cells of the human endocrine and exocrine pancreas. Nat Metab 2021 Feb;3(2):149-165.doi: 10.1038/s42255-021-00347-1.
5) Liu Y et al. Paradoxical sex-specific patterns of autoantibody response to SARS-CoV-2 infection. J Transl Med 2021 Dec 30;19(1):524.doi: 10.1186/s12967-021-03184-8.
6) Unsworth R. New-Onset Type 1 Diabetes in Children During COVID-19: Multicenter Regional Findings in the U.K Diabetes Care 2020 Nov;43(11):e170-e171. doi: 10.2337/dc20-1551. Epub 2020 Aug 17
7) Metwally AA et al. COVID-19-Induced New-Onset Diabetes: Trends and Technologies Diabetes 2021 Dec;70(12):2733-2744. doi: 10.2337/dbi21-0029. Epub 2021 Oct 22.
8) Khunti K et al. COVID-19, Hyperglycemia, and New-Onset Diabetes. Diabetes Care 2021 Dec;44(12):2645-2655. doi: 10.2337/dc21-1318. Epub 2021 Oct 8.
9) Wu C. et al. Risk Factors Associated With Acute Respiratory Distress Syndrome and Death in Patients With Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med 2020.
10) Wu Z et al. Prevention of chronic diabetic complications in type 1 diabetes by co-transplantation of umbilical cord mesenchymal stromal cells and autologous bone marrow: a pilot randomized controlled open-label clinical study with 8-year follow-up. Cytotherapy 2022 Jan 24;S1465-3249(21)00825-2. doi: 10.1016/j.jcyt.2021.09.015
11) Kenyon NS et al. Extended survival versus accelerated rejection of nonhuman primate islet allografts: Effect of mesenchymal stem cell source and timing.Am J Transplant. 2021 Nov;21(11):3524-3537. doi: 10.1111/ajt.16693. Epub 2021 Jul 2.PMID: 34008325
12) Lanzoni G et al. Umbilical Cord Mesenchymal Stem Cells for COVID-19 acute respiratory distress syndrome: A double-blind, phase 1/2a, randomized controlled trial. Stem Cells Transl Med. 2021 May;10(5):660-673. doi: 10.1002/sctm.20-0472. Epub 2021 Jan 5. PMID: 33400390
13) Zanirati G et al. Stem cell-based therapy for COVID-19 and ARDS: a systematic review. NPJ Regen Med 2021 Nov 8;6(1):73. doi: 10.1038/s41536-021-00181-9. PMID: 34750382
14) Kouroupis D et al. Umbilical Cord-derived Mesenchymal Stem Cells modulate TNF and soluble TNF Receptor 2 (sTNFR2) in COVID-19 ARDS patients. Eur Rev Med Pharmacol Sci. 2021 Jun;25(12):4435-4438. doi: 10.26355/eurrev_202106_26156. PMID: 34227081
15) Quattrin T et al. Golimumab and Beta-Cell Function in Youth with New-Onset Type 1 Diabes. N Engl J Med. 2020 Nov 19;383(21):2007-2017. doi: 10.1056/NEJMoa2006136. PMID: 33207093