Stem cell therapy for Parkinson’s disease is likely one of the most promising approaches to not only slow down the disease, but also reverse it.
However, there are many important things to take into account when assessing cell therapies for Parkinson's disease.
Furthermore, be (very) weary of companies offering stem cell therapies for Parkinson’s disease. Nearly all of them use unapproved, untested “therapies”, often with low-quality or non-existing cells, and could actually be dangerous.
Luckily, various companies and universities are currently testing novel (stem) cell therapies for Parkinson’s disease (learn more about clinical trials for Parkinson’s disease here).
Generally, stem cell therapy for Parkinson's disease involves transforming stem cells into dopamine-producing cells, which are then implanted into the brain (Parkinson's disease is mainly caused by the loss of dopamine-producing cells).
However, many of these approaches differ substantially. Below you find some important things to take into account when assessing cell therapies.
1. Fetal cells versus pluripotent stem cells
Around the 1990s, physicians such as Lindvall, Björklund, and colleagues transplanted dopamine-rich tissues dissected from fetal ventral mesencephalon (fVM) into Parkinson’s disease patients, providing the first “proof-of-concept” for cell therapy for Parkinson’s disease (R).
Fetal ventral mesencephalon (fVM) cells are derived from the midbrain of aborted fetuses (typically 6 to 9 weeks old). This region contains large amounts of dopamine-rich cells, the cells which are lost in Parkinson's disease.
Various such studies showed long-term improvements in some patients (R,R,R,R). However, subsequent double-blind, sham-controlled studies showed that these positive benefits were in most cases statistically insignificant.
Additionally, around 30% of patients developed a serious side effect: graft-induced dyskinesia (GID), due to the immune system of the host attacking implanted cells.
So despite initial enthusiasm, this approach has been abandoned due to lack of benefits, the risk of immune rejection, and being ethically contentious. It was also very difficult and time-consuming to acquire these cells, which had to be extracted from fetuses (typically requiring 6 to 8 fetuses per patient).
Therefore, scientists looked at other approaches to acquire dopaminergic cells, such as using pluripotent stem cells (see further below).
2. Embryonic stem cells versus induced pluripotent stem cells
Pluripotent stem cells are very powerful stem cells, in the sense they can differentiate into any cell type, including neurons. They can also divide without limitations, so they can be grown in large supplies.
There exist two types of pluripotent stem cells:
- Embryonic stem cells (ESCs): these are derived from early-stage embryos. Therefore, their use is to some people ethically contentious. These cells also can pose immunological rejection risks, given they are different cells than the host's cells. Also, ESCs are often multiplied many times in the lab to grow large quantities of them for multiple patients, increasing the risk of mutations in their DNA.
- Induced pluripotent stem cells (iPSCs): these cells are created by reprogramming somatic cells into stem cells. For example, skin cells of an adult with Parkinson’s disease can be taken, reprogrammed into iPSCs in the lab, and then these iPSCs are transformed (“differentiated”) into dopaminergic neurons, which are then implanted into the brain.
There is much less risk of immune rejection, given these cells derive from the same patient, while also sidestepping ethical concerns (no need for embryos).
However, the reprogramming and differentiation process can introduce genetic and epigenetic abnormalities that must be carefully monitored.
Furthermore, it should be checked that no stem cells are still remaining among the to-be-transplanted dopaminergic cells, given these stem cells could theoretically give rise to tumors. There should also not be serotonergic neurons in the cell batch, which could cause immune responses like graft-induced dyskinesia.
A 69-year old patient was transplanted with iPSC-derived dopaminergic cells, not needing immune suppression. Some clinical symptoms stabilized or improved 24 months after transplantation (R):
Fig.: Panel A shows scores on the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III. Scores (range, 0 to 132, with higher scores indicating worse parkinsonian motor signs) are shown both after overnight withdrawal of levodopa (“off”) and at the peak dose of levodopa (“on”). Panel B shows scores on the 39-item Parkinson’s Disease Questionnaire (PDQ-39) assessing quality of life. Scores range from 0 to 156, with higher scores indicating worse quality of life.
3. Immunosuppression (or not)
When cells are transplanted from a donor to a host (e.g. fetal or embryonic cells), mostly drugs need to be taken to reduce the risk of immune rejection.
Different immunosuppressive drugs and regimens are used (e.g. cyclosporine, azathioprine, prednisone or combinations thereof), which can also impact the success (and side-effects) of the treatment.
As mentioned earlier, dopaminergic cells derived from induced pluripotent stem cells (iPSCs) do not require immunosuppression, given these cells come from the same patient.
Not needing immunosuppression would be preferred, given immunosuppressive drugs have significant side effects, including substantially increasing risk of cancer and kidney failure.
4. Matched versus non-matched cells
In most cases, induced pluripotent stem cells (iPSCs) are derived from the patient himself.
However, this is a time-consuming and complex process: it requires extracting differentiated cells (like skin cells) from the patient, changing them into stem cells, and then into dopaminergic neurons.
Ideally, there would be “off-the-shelf” iPSCs, which can be used in many patients. To prevent immune-rejection (given they come from another person, a donor), these iPSCs could be matched. Matched cells means that the donor cells have specific combinations of immune receptors which “match” the immune receptor combinations of the host patient.
This minimizes the risk of immune rejection and the need for immunosuppressive drugs.
It is estimated that iPSC lines derived from approximately 140 unique donors (each with unique immune receptor combinations) would be sufficient to cover up to 90% of a specific population.
However, an immune response may still occur even with HLA-matched cells (for example due to existing H-Y minor histocompatibility antigens, or innate immunity resulting from natural killer cells).
5. Dopaminergic neurons versus precursor cells
Some studies suggest that dopaminergic precursor cells graft and survive better than dopaminergic neurons.
Precursor cells are somewhat in-between stem cells and neurons, enabling them to have more plasticity.
Dopaminergic neurons are completely differentiated cells; they have no real stem-cell like qualities left.
6. Quality of the cells
When cells are reprogrammed and grown in the lab, they are exposed to many stress factors, such as a higher oxygen content, light, movement, no or less supporting cells, different nutrients, changes in acidity (pH), oxidative stress, calcium imbalance, lipid oxidation, etc.
After growing and multiplying these cells, they are also cryopreserved, which can also stress the cells.
Such stress can cause mutations in the genome and epigenome of the cells, and damage them generally, reducing their quality, viability and resilience.
So when growing and multiplying cells in the lab, it’s paramount to keep the cells as healthy as possible, and use specific culturing methods and mediums. For example, cells grown in 3D cultures seem to survive less well compared to cells grown in 2D cultures.
Before implantation, cells ideally should be tested for mutations in the genome and epigenome due to these reasons.
7. Pre-treatment of cells
Most implanted cells (more than 90%) die due to the stress and shock these cells experienced when being grown in the lab, harvested, and injected into the body.
To improve the resilience and grafting of cells, pre-treatment of cells with growth factors like basic fibroblast growth factor (bFGF) or glial cell line-derived neurotrophic factor (GDNF) can significantly enhance the survival of implanted dopaminergic cells.
Adding bFGF doubles survival rate, but continuous delivery of bFGF through co-transplantation of bFGF-overexpressing fibroblast cells even led to a 10-fold increase in survival.
Adding calcium channel blockers (reducing calcium toxicity in cells) and lipid oxidation inhibitors (preventing oxidation of the fragile cell membranes of cells) also improves their survival.
Scientists are developing many other approaches to increase resilience and grafting of implanted cells, such as using scaffolds or hydrogels to support and protect the cells.
8. Implantation site
In Parkinson’s disease, cells are lost in the substantia nigra, a region in the midbrain. However, in most surgical procedures, dopaminergic cells are implanted into other, higher regions in the brain, namely the caudate or putamen.
The reason for this is that if cells would be implanted in the substantia nigra, it would take years for these cells to grow axons (connections) with the higher brain regions (caudate or putamen).
Despite this, in some studies cells were also implanted in the substantia nigra.
Furthermore, in some studies, cells are implanted only in one hemisphere (one side) of the brain (unilateral), while in other studies cells are implanted in both sides (bilateral).
It could be that implanting cells in both sides of the brain, and in the putamen (and also in the substantia nigra) could be the best regions to implant them.
9. Amount of cells injected
The number of cells that are injected is also important. It’s estimated that at least 100,000 cells need to successfully graft and survive to benefit from a cell treatment.
When cells are injected, most of them die due to stress and grafting problems. Therefore, it’s important to inject sufficient numbers of cells to increase the chance that at least some cells graft.
For example, in one clinical trial, it was found that injecting 2 million cells lead to significantly better outcomes than injecting “only” 900,000 cells.
Conclusion
(Stem) cell therapy holds great potential for Parkinson’s disease, but it still has a lot of challenges.
Carefully assessing the source of the cells, production and expansion process, quality, and method of cell transplantation, as well as the steps taken to improve survival and integration, will be crucial for the success of these therapies.
Learn more about the latest trials for Parkinson’s disease, including stem cell therapies, here.
Learn more about the best foods for Parkinson's disease here.
