Fact-checking stem cell stroke therapy: hope but not there yet

Stem cell stroke therapy research has generated buzz over the years.

The goal of today’s post is to fact-check claims about supposed stem cell stroke therapies and educate readers on where clinical research stands. There is some real hope here in the long run, but things have been greatly exaggerated at times. Some clinics are even already selling unproven infusions, which I see as very risky with little-to-no chance of benefit.

What is a stroke? | Stem cell stroke therapy | Clinical trials & risks | Gordie Howe | Future hope | References

Stem cell stroke therapy, stem cell stroke
Stroke therapy studies in mice. “Giving 3K3A-APC to mice with stroke-induced brain damage dramatically increased the production of new neurons (labeled in red) from neural stem cells implanted next to the injured area. Berislav Zlokovic, M.D., Ph.D., USC”. Image from the NIH website.

What is a stroke?

A stroke occurs when part of the brain doesn’t get enough blood. Brain tissue is very sensitive to oxygen and nutrient levels. This means that during a stroke many brain cells can rapidly die. For that reason, strokes are emergencies. Every minute can count. The CDC has a useful explainer on how to tell if you or a loved one are having a stroke. 

There are two main kinds of strokes.

In ischemic stroke, a blood clot clogs up blood vessels supplying parts of the brain. The brain region supplied by the clogged blood vessel quickly malfunctions and can eventually die. Sometimes people call this a “brain attack” because it is similar in physiological cause to a heart attack, which also involves a clogged blood vessel.

In contrast, in a hemorrhagic stroke, blood vessels break in the brain and the pressure from bleeding can kill brain tissue.

We’re also much more aware these days of transient strokes or mini-strokes.

These are often called transient ischemic attacks or TIAs. Data over the past couple decades have shown that TIAs need to be taken very seriously. They sometimes proceed to strokes. As many as one-third of people who have had a TIA will go on to have a full-blown stroke without treatment in following years.

At their time of occurrence, TIAs are emergencies too. They may just be the beginning of a regular stroke.

TIAs can also cause some small injury to the brain, which may be reversible.

Stem cell stroke therapy

How is stroke treated?

Today the main, acute treatment for an ischemic stroke is to get the clogged blood vessel open. Doctors give patients clot-buster medicines like TPA that can dissolve the clogs.

In hemorrhagic stroke doctors urgently try to address the bleeding and lower blood pressure.

Why would someone think about treating stroke injury of any kind with stem cells?

Stem cell infusions are not likely to be useful in acute treatment for a stroke. In fact, infusions of stem cells of certain kinds could make an ongoing stroke worse by leading to more clots.

So how could stem cells possibly be useful in strokes?

The main goals behind trying to development stem cell therapy for strokes are to try to repair damage to the brain such as by reducing inflammation or grow new brain tissue. There’s an urgent need as right now there aren’t effective therapies to treat stroke tissue damage if the acute treatments cannot prevent it at the beginning.

There are two main ways that stem cell stroke therapy could be helpful to address damage longer term.

First, infusions of adult stem cells could reduce inflammation in the brain and aid the brain in healing itself. Second, infused neural stem cells or more specialized brain cells made from stem cells, could replace dead or damaged brain cells. In this second scenario, we don’t know how well the new brain cells or areas of tissue would integrate into the existing brain structure.  The possible results depend greatly on the kind of cells used.

A PubMed search for review articles found some recent ones that are interesting on cell therapy for stroke, some propose some more specific mechanisms could be at play.

Many studies of these kinds of approaches have initially been conducted in mice. Here is an example of a recent stem cell stroke study in mice highlighted by the NIH.

stem cell stroke therapy, stem cells for stroke, stem cell stroke
A map of clinical trial listings of stem cell stroke therapy. Clinicaltrials.gov map.

Clinical trials on stem cells for stroke

A search on Clinicaltrials.gov for listings involving stem cells for stroke of any kind found 100 clinical studies. Of these, ninety listings were interventional, which means they are or are planning to try to actively treat stroke.

Earlier in the year, Athersys stock got slammed for disappointing results in Japan in a Phase 2/3 study. The stock has plummeted this year, down 97% YTD. They do have other work ongoing including the MASTERS-2 clinical trial. Let’s hope for better results.

You can see in the map above that most of the stroke studies involving stem cells are in the U.S., China, and Europe.

Scanning through the trial listings, some have a strong rationale, which is encouraging. However, others don’t necessarily make much sense to me as a stem cell biologist. For a particular kind of stem cell there should be a solid foundation of data including preclinical studies before trying it out in people. Otherwise it’s a shot in the dark.

Risks. Any stem cells given as a possible stroke therapy will have risks. For instance, neural stem cells infused directly into the brain or CNS have some potential to lead to tumor formation. There is also the possibility for the cells to change into undesired cell types or alter brain function in unexpected ways.

The use of MSCs or mesenchymal cells could also have unexpected outcomes, although their potential to form tumors is relatively lower than other cell types. One worry is scar formation inside the brain even unvalidated preps of MSCs are infused.

Infection is always a concern with stem cell infusions too including when given via IV administration or directly putting cells into the brain.

We don’t have a clear picture yet of how often possible side effects might occur.

The Gordie Howe case & hype

Unfortunately, the idea of stem cell stroke therapy has gotten ahead of the clinical science. For more than a decade, some folks have been selling various supposed stem cell stroke therapies. Stroke patients and their families are often targeted with overexuberant marketing in this space.

We’ve also seen celebrities who have had strokes become the center of discussions over whether stem cells for strokes is a good way to go or not. Some of this can start to feel like advertising.

Here are some articles you might check out on celebrities and stem cells for stroke:

The Gordie Howe case involved a U.S. firm called Stemedica.

There are still numerous stem cell clinics pitching stem cells for stroke including Mexico’s Novastem.

However, I believe the clinics still don’t have the strong clinical trial data to back that kind of thing up.

No stem cell therapies for stroke are approved in the U.S.

It doesn’t help when stem cells for strokes are depicted in inaccurate ways on TV. For example, check out this past piece: Family Guy Cartoon Blows it on Stem Cells for Stroke.

Future of stem cell therapy for stroke

We need to see far more and stronger clinical trial data to know what cells and which kind of approach might be best, if any. So far, the published clinical trials are mostly not designed or powered to tell us much. For example, unblinded, non-controlled, and non-randomized small studies are at best just a starting point. These are sometimes oversold though to the media and patients.

Sometimes even academic institutions have gotten ahead of the data and there’s risk there of giving patients and families false hope.

Still, I am hopeful overall that eventually one or more therapies might be proven safe and effective. In the meantime, no one should be selling stem cells or similar approaches for stroke. Further, researchers should discuss their clinical trial findings cautiously as well.

References and notes

9 thoughts on “Fact-checking stem cell stroke therapy: hope but not there yet”

  1. I continue to be worried about mesenchymal stem cells. This is why. MSCs got the jump on cell therapies using cell types derived from iPSCs or hESCs. The reasons are simple: First, stromal cells (aka MSCs) are easy to get- they exist all over the body and are easily accessed as fresh cell preparations or as expanded cell cultures. This means that there is no one MSC – they vary widely depending on how and where they come from. Second, the transplanted cells don’t engraft, so they are in the body for a short time. This means that they don’t have time to become cancerous.

    Neither of these qualities suggests that they would be good as therapeutics. But both qualities make it easier to perform Phase 1 safety trials for whatever disease or injury one chooses. The problem is that if the mechanism of action of the cells – what about them makes them helpful – is not known, the product can’t be improved. And worse, if in subsequent experiments the cells stop working or work better, you won’t know why.

    There are now a number of clinical trials underway that use cell types derived from pluripotent stem cells. MSCs were used to try to treat age-related macular degeneration (AMD) – they proved to be not only ineffective, but dangerous. Now there is a clinical trial at the NIH for AMD underway using an iPSC-derived product, retinal pigment cells, whose mechanism of action is known.

    The mechanism of action is known for an epilepsy therapy by Neurona using hPSC-derived inhibitory neurons; it is known for the three trials underway for Parkinson’s disease, using hPSC-derived dopamine neurons. Vertex is testing hPSC-derived pancreatic islets for treatment of Type I diabetes.

    So it is possible to treat people with cell types that make sense for a specific disease. It just takes time, knowledge, and skill to make the right cell type for each disease.
    As hPSC-derived cell therapies begin to become approved, the motivation for using MSCs with their vague effects will decrease, so the only question for me is, if MSCs are the best cell type for some use, what will it be?

    1. @Jeanne. Good points. The other thing though is that we can’t be sure that certain cells under the MSC umbrella, particularly after culturing for long periods in vitro and/or gaining mutations, might actually engraft and pose a threat that way. Rigorous biotech firms probably are appropriately very careful with MSC or related cell characterization and culturing. Athersys safety data that I’ve seen has been good.

      1. This is an interesting article I read today (source Google search), it seems the specific cellular characteristic of MSCs should be assayed prior to use. Parent’s guide to Cord Blood Foundation, April 2022, Title: “Therapeutic MSC infusions: When more of a good thing is not always better”

        During my last search for MSC clinics in Mexico just over the border it seems the number of clinics has increased. It would be interesting to know how many American citizens travel to these clinics for treatment. I would surmise that some business statistical analysis is justifying more clinics to get into the business.
        I think the US should participate in this market so as to ensure the many safety concerns are addressed.

    2. This article from PubMed expounds on the characteristics of different sourced MSCs, and bio pathway mechanisms.
      PubMed May 3, 2021, Title: “Biological Characteristics of Umbilical Cord Mesenchymal Stem Cells and Its Therapeutic Potential for Hematological Disorders”
      The regenerative characteristics and use of these cells should be fast tracked.

      I have been looking into how long the MSCs stay intact in the body after infusion. The answers I’ve seen range from 3 to 7 days, 14 days, and 21 days. I’ve also heard that they can stay intact in the body without differentiating for over a year.
      I went to a clinic in Mexico, 9/26/21 and had 300 million umbilical cord cells infused, I was told that I might not feel any discernible effect until 3 months later, why would the timeline be 3 months ?
      I did feel a change in my body 2.5 months later my energy level was significantly improved, and the CBC & CMP with C-RP I have on a regular basis, showed a significant drop in C-RP level.

  2. You didn’t take the time to mention the biggest Phase 3 clinical trial in stroke using a cellular therapy that’s ever taken place, that’s enrolling patients right now. MAPC cells, similar to MSCs, have demonstrated an almost pristine safety profile with no evidence of tumors in any patients in at least 6 clinical indications. Your article would be cutting edge in 2010. Cell therapy for strokes have moved forward. The proposed mechanisms of action for how the cells are purported to provide benefit have advanced. There was a Nature Neurology review on this very subject 2 weeks ago. The MASTERS-2 trial has received RMAT, SPA and Fast Track designations from FDA, and a positive opinion from EMA. The TREASURE trial in Japan using the same cells may be considered for Conditional Approval under Sakigake in Japan. Paul, please, do some homework.

    1. @Robert,
      On the whole my post rightly reflects that no cell therapy is approved and the data so far haven’t been that convincing on efficacy. The core mechanisms of possible cell therapy repair are the ones I mentioned. RMAT, SPA, and Fast Track are positive, but in the end it’s the Phase 3 data that is needed to see the promise. News like this from earlier in the year isn’t encouraging: https://www.fiercebiotech.com/biotech/athersys-stock-plunges-60-wake-stroke-stem-cell-therapy-missing-endpoint. I hope MASTERs-2 brings some much needed good news.

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