I’ve been watching as the number of registered stem cell-related clinical trials for the novel coronavirus (SARS-CoV-2) disease COVID-19 continues to spiral upward, mostly in China.
During the last two weeks, I’ve been trying to carve out a bit of time to look at these actual trials in more depth, but I admittedly haven’t gotten very far as I’m super busy with other stuff.
What I have read so far in the COVID-19/stem cell trial descriptions hasn’t convinced me that stem cells are likely to be useful for COVD-19. The rationales just seem shaky to me.
Could I be flat-out wrong about that?
I doubt it, but over the last few days, Chinese researchers have posted two preprints claiming that mesenchymal stem cells (MSCs) had success in helping coronavirus patients, and this hit the media there.
In fact, there is already a claim of saved lives.
Journalist Stephen Chen wrote about these supposed “successes” in a news article in the South China Morning Post. The headline seems way too exuberant in my view: “Coronavirus: critically ill Chinese patient saved by stem cell therapy, study says.”
Here are the two big key bullet points underneath the news article’s title, which also reflect upbeat views:
’65-year-old woman in Kunming hospital intensive care unit showed no adverse effects to her first shot and after two was up and walking again, researchers say
Results ‘could be very important and inspire similar clinical practices in treating critically ill Covid-19 patients’
I dug up what I think are the two preprints that are the focus of Chen’s story:
- Transplantation of ACE2- mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia (key claim, “MSCs could cure or significantly improve the functional outcomes of seven patients with COVID-19 pneumonia in 14 days without observed adverse effect.”) See image of 1st worsening and then improving chest x-rays above from Figure 2.
- Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord mesenchymal stem cells (key claim, “Our results suggested that the adoptive transfer therapy of hUCMSCs might be an ideal choice to be used or combined with other immune modulating agents to treat the critically ill COVID-19 patients.”)
I still can’t help but feel skeptical about these reports after skimming them.
I hope I’m wrong, but this all (especially the news article) gave me some kind of dark deja vu from the old days of stem cell clinics and even some others claiming that they could get paralyzed people up and walking again fairly quickly.
Of course, the reality is that these are just small clinical case reports and must be interpreted cautiously so far as spontaneous recoveries cannot be rule out, but that’s kind of how it is doing quick clinical studies during an outbreak.
Isn’t it? What do you think?
From towards the end of Chen’s article, we have this from one of the investigators:
“According to Dr Li Honghui, who is involved in similar trials at Loudi Central Hospital in central China’s Hunan province, stem cell injections can deliver significant results within three days.
“We cannot stick to the rules, we must be bold and innovative,” he was quoted as saying in a report by Hunan Daily last week.”
We’ll see where this all leads on the stem cell-novel coronavirus front. I hope we don’t see unproven clinics tapping into this somehow such as for claims about lung health more generally or something.
Lets not throw away stem cells out of the basket just because of unforeseen fears created largely by stem cells scientists themselves and I agree with Richard Vulliet’s view, There is a merit out there and much more is on the way in term of benefits, given the efforts made by entrepreneurs who are putting in their own money & time into it.
Cultured stem cells in Panama have been given to over 9,000 patients and not reported side effect. This is a treatment that will boost the immune system so what are we waiting for. I hope they fast track this through as there would more then enough data for approval in the US for culturing Wharton’s jelly for culture into billions of life saving cells.
Hi Paul,
There is an explanation, and an immediate solution here. Can someone please help ?
– EXPLANATION:
LIF is absolutely required to oppose the cytokine storm in the lungs during viral pneumonia. (QUINTON . J Imm 2012; FORONJY et al.. Immunology 2014)
Although MSC release LIF, this is not a practical solution.
– IMMEDIATE SOLUTION:
cGMP-LIFNano with regulatory approval : I am working with the FDA and MHRA to that end. We propose delivery both by inhaler plus i.v. to reduce vascular leak: we have already completed preclinical safety. SCALE OF NEED: manufacture is in place 3000L and the nano formulation increases potency of LIF 1000x fold.
My company (www.LIFNano.com) can move on this immediately BUT need the funds. Alas my bid to the UK MRC was bounced on Friday 6th, however everything remains in place to start the work. Any help / guidance to funds most welcome.
Should I try China? If so, to whom.
Are any Pharma interested ? There is IP and equity.
The World Bank have a call out too.
Happy to work together with others to expidite this…
Su
Paul,
I find that your skepticism of these preliminary observations as somewhat misplaced and falling into the “we need “double-blind controlled clinical trials” saw. Yes, we do need the trials to form the foundation of all rational therapy. But when somebody tries something new, your unbridled skepticism takes over. Implications by you and statements by others suggest that the motive here was “an unscrupulous stem cell clinic motivated only by profit.” This statement demonstrates a disturbing lack of perspective about therapeutics.
First, there are very few fatal viruses. Rabies being a notable exception. Most viruses disrupt endothelial or epithelial barriers leading to secondary bacterial infections. In many cases, the patient succumbs to the secondary bacterial infection, not the virus. With COVid19’s case fatality rate of about 3%, I suspect that this is also the case (e.g. the respiratory epithelium is seriously damaged and the patients are dying of bacterial complications). The swine flu pandemic of 1918 which killed somewhere around 50 million people (Wikipedia), was before the emergence of modern antibiotics. It has not been repeated due to the development of modern antibiotics.
So lets examine your skeptical comments concerning the use of MSCs in COVId19. First, if the virus is seriously damaging the respiratory epithelium, could MSCs help to restore the integrity of this barrier? Certainly, there is nothing in the brief reports and secondary reports that would suggest this, but it is consistent with many of the wound healing studies that have been conducted over the past many years. I believe that it is possible that MSCs would help restore the barriers. Second, could MSCs help with secondary bacterial infections? I have seen multiple papers, some by serious investigators, that MSCs do help during model bacterial infections. Thus, I think that your skepticism is premature here.
Just as a competent physician would not use classical antibiotics in an uncomplicated viral infection, she most certainly would in one when the patient returned five days later “hawking up lime green goobers” (bacterial infection). I would be surprised if MSCs had any effect on the viral part of the infection. However, I would reserve judgement when dealing with secondary complications.
Another support that there may be something to MSCs being protective against COVid19, a caller into Ira Plato’s Science Friday made the comment that there have been no (or few) children that have died from COVid19. Thinking back, I have not heard of any. According to Prophet Caplan, MSCs peak in the early and teen age years. This may be selective news coverage, but the adage that “if it bleeds, it leads” would apply here. I have not yet seen a front-page cover with “a woman holding a child dying of COVid19.” To the best of my knowledge, most of the patients that have succumbed to COVid19 have been elderly in nursing homes or on cruise ships.
Clearly, there is no enough information about MSCs and COVId19, but I think the investigators reports were to inform others of this possibility. Not to try and convince the scientific world that MSCs cure COVid19. Skepticism is justified but not for the reasons described. In these patients, it is likely that they were “losing them”, so they loaded them up with high powered antibiotics. The patients continued to decline, and somewhere near the point of no return, they then administered MSCs. The knowledgeable skeptic would recognize that maybe the noted improvement may have been due to the onboard antibiotics having a delayed effect and the stem cells had little to do with it. However, considering that wound healing studies and bacterial response studies with MSCs suggest that the MSCs may have had a beneficial effect. The investigators probably “did no harm” consistent with Hippocrates and may have saved the patient. Future studies will tell but “arm chair quarterbacking” (America’s favorite sport) really does not help. Opinions are worth what you pay for them.
Richard
We are not in a situation where we may implement a Phase III without other therapeutics. the patients being under treatment, and often times multi-drug, would the MSC on top of that cause miracles? I strongly doubt about it, a feeling reinforced in view of what the other scientists mentioned in the comments.
Incidentally, one of the trial says “combined with other immune modulating agents”.
Corticosteroid inhalation, anybody? The are a couple of cases where the clinician believe that the corticosteroid ihalation (ciclesonide) on 3 COVID-19-positive elderly patients with moderate pneumonia resulted in a spectacular recovery.The same as with MSC can be said here: too good to be true. To check if steroids work, one may try conventional ones e.g., budesonide or fulticasone to see if the remission is attributable to the sole ciclesonide.
For stem cell therapies, however, one cannot implement such comparative trials, will have to adminster the MSCs ongoing treatment, preventing the results to be interpreted for the effect of MSC alone.
What the trials are about to brig in terms of scientific evidence, only the future will tell.
Yet, that future, to me, does not look bright at all…
Difficult to keep cells alive in a nebulizer and likely they’d be killed by mucous membranes, which are a natural barrier to foreign, vegetative cells.
Paul, you say that the (therapeutic) rationale seems shaky. This is also the case for many purported stem cell therapeutics offered at the moment for anything from coronavirus to autism. Whereas safety (and eventually) efficacy need to be demonstrated in order for a therapy to become approved for use, there is no FDA qualifier for scientific rationale (the mode of action) in order to carry out a clinical trial. This is what leads to the unsubstantiated claims we often see with the title “FDA approves clinical trial for [insert illness] using adipose derived stem cells.”
Sellers then leverage the “FDA approves…” statement to con the unsuspecting patient that this is an approved therapy or at least has some credibility (= hope). Usually this would all come crashing down in a Phase II clinical trial (or in preclinical work) where efficacy or benefit cannot be shown.
Of course there are many back doors to avoid the critical studies (e.g. RMAT) and until the process requires solid preclinical data we will inevitably have MSCs claimed for whatever is needed most urgently. As a matter of interest, how many MSC or SVF trials have actually shown a benefit over standards of care (as measured by a true independent metric)? I guess not many.
Wondering if it were introduced with a nebulizer what results might be?
Allogeneic umbilical cord MSC’s would not necessarily need to be expanded ex vivo. It would limit the number/therapeutic dose if not expanded, but they can be isolated from Wharton’s jelly or even better from placental perfusion (disclaimer: I have 2 issued patents on placental perfusion). Still these would be allogeneic and not “homologous” and would, therefore, would require clinical trials. One thing that is known, infused “Stem Cells” (whether or not they’re “MSC” or some other type of multipotent lymphocyte precursor) are trapped in the lungs as a natural course of blood flow and physiology. I am skeptical any benefit, but for this reason there is a possibility.
@Jim, I thought about the lung trapping too, but I thought that kind of is a good place for MSCs to die rather than do something useful.
If something looks to be too good to be true, it probably isn’t true. Just an old saw from the world of finance and news. I have no knowledge of the specifics of the ostensible work. But I have considerable knowledge about how fear, desperation and greed can regularly combine in malevolent ways. Another way to describe this situation is that it is a side effect of the coronavirus that we all should be wary of. We are depending on you, Paul, and your colleagues to keep us straight.
@David, This does seem too good to be true and the hype feeling to some of it doesn’t help.
Allogeneic umbilical cord MSC’s would have to be a cultured product and approved by the FDA as a drug product. Rapid clinical trials would have to be performed to demonstrate effectiveness. I believe that it should be investigated as a therapeutic method to treat critically ill people who are or become infected, but it is unlikely depending on how severe the pandemic develops and what other therapeutic products and measures are introduced.