New human clinical trials using derivatives of pluripotent stem cells in China for Parkinson’s Disease (PD) have raised expectations and some eyebrows. PD is a neurodegenerative condition, sometimes diagnosed or followed by PET scans such as the one at left, characterized by loss of dopaminergic neurons leading to severe and sometimes life-threatening symptoms.
Pluripotent stem cells are powerful as their name implies and they have great clinical potential, but if they are not utilized properly they have robust tumor forming potential. This risk can be substantially reduced to near zero if the cells used in any given clinical trial are fully differentiated from the embryonic stem cells (ESC) or induced pluripotent stem cells (IPSC) and subject to thorough pre-transplant vetting such as biological, genomic, and epigenetic screening.
The Chinese Parkinson’s Disease trial using ESC as a starting point is unusual because the derivatives that will be transplanted are not fully differentiated cells, but rather neural precursor cells. From a Nature piece by David Cyranoski on these ESC trials:
“Both studies will take place at the First Affiliated Hospital of Zhengzhou University in Henan province. In the first, surgeons will inject ES-cell-derived neuronal-precursor cells into the brains of individuals with Parkinson’s disease. The only previous trial using ES cells to treat Parkinson’s began last year in Australia; participants there received stem cells from parthenogenetic embryos — unfertilized eggs that are triggered in the lab to start embryonic development.
In the other Zhengzhou trial, surgeons will take retinal cells derived from ES cells and transplant them into the eyes of people with age-related macular degeneration. The team will follow a similar procedure to that of previous ES-cell trials carried out by researchers in the United States and South Korea.”
Both trials will be led by Qi Zhou and for Parkinson’s Disease the teams have selected ten candidate patients for trial participation who they believe are good matches to the allogeneic ESCs in the bank.
Neural precursors are multipotent, often highly proliferative cells that can have their own kind of tumorigenic potential. This makes the new China Parkinson’s study inherently risky and raises a number of questions. Will the ESC-derived precursors mostly differentiate into the desired dopaminergic neurons following transplant? Even if most do, could some of the other precursors make distinct, undesired cell types? Could some of the transplanted precursors continue to proliferate within the recipient brain and cause problems via benign growth? What about potential malignant growth? There is also potential that the patients will reject the allografts.
Unfortunately the pre-clinical data from this team remains unpublished so the stem cell community does not have concrete, peer-reviewed data to go on to address such questions or concerns. Some stem cell/Parkinson’s experts have concerns. For instance, Jeanne Loring was quoted by Cyranoski about her concerns related to the fate of the transplanted precursors, “Not knowing what the cells will become is troubling” and Loring had this comment when I asked her for additional thoughts:
“From the Nature piece readers may not have clearly understood that the different clinical trial teams are using somewhat distinct cell types produced from ESCs and those differences have important potential functional implications. For instance, we are using immature DA neurons, that haven’t arborized much in the dish. Malin Parmar is using slightly less differentiated cells. The point is that we get >90% live cells after dissociation. The cells that the Chinese group and International Stem Cell Corp. are using are actually better termed neural stem cells- their fate is neuronal but not specific. Our cells are committed to the DA lineage. They’re hoping for trophic effects, not cell replacement. Also, the identification of dopamine neurons has to include their function- synthesis and release of dopamine when stimulated.”
Lorenz Studer was also concerned according to Nature:
“Lorenz Studer, a stem-cell biologist at the Memorial Sloan Kettering Cancer Center in New York City who has spent years characterizing such neurons ahead of his own planned clinical trials, says that “support is not very strong” for the use of precursor cells. “I am somewhat surprised and concerned, as I have not seen any peer-reviewed preclinical data on this approach,” he says.”
Clinical trials being based on unpublished data is not that unusual and regulators get to see the data even if we do not, but it raises risks. Both the Chinese and Australian teams are nonetheless enthusiastic:
“But Zhou and the Australian team defend their choices. Russell Kern, chief scientific officer of the International Stem Cell Corporation in Carlsbad, California, which is providing the cells for and managing the Australian trial, says that in preclinical work, 97% of them became dopamine-releasing cells.”
The reported 97% specificity is astonishingly good if correct. Such specificity is not easily obtained even in vitro under very defined conditions, whereas in vivo inside a transplant recipient’s brain there is a high degree of complexity with a mix of growth factors, extracellular matrix, cellular interactions, and potential niche conditions.
It’s not clear to me why transplanted ESC-derived neural precursors could be expected to almost entirely adopt one very specific fate in vivo. Are they pushed firmly in a certain direction prior to transplantation? The possible advantages of using precursors may be that they can potentially yield higher net engraftment since there remains proliferative activity and the cells may respond to in vivo signals, potentially yielding better functional engraftment. Precursors may also survive transplant better since neurons are complex cells that can be damaged during injection into the brain.
Is that precursor potential worth the risks? We’ll soon find out, but I see it as a high-risk approach. Still precursor-based trials such as these will be fascinating to watch.