For my entire career as a neurologist, spanning three decades, I have been hearing about various kinds of stem cell therapy for Parkinson’s Disease (PD). Now a Phase I clinical trial is under way studying the latest stem cell technology, autologous induced pluripotent stem cells, for this purpose. This history of cell therapy for PD tells us a lot about the potential and challenges of stem cell therapy.
PD has always been an early target for stem cell therapy because of the nature of the disease. It is caused by degeneration in a specific population of neurons in the brain – dopamine neurons in the substantial nigra pars compacta (SNpc). These neurons are part of the basal ganglia circuitry, which make up the extrapyramidal system. What this part of the brain does, essentially, is to modulate voluntary movement. One way to think about it is that is modulates the gain of the connection between the desire the move and the resulting movement – it facilitates movement. This circuitry is also involved in reward behaviors.
When neurons in the SNpc are lost the basal ganglia is less able to facilitate movement; the gain is turned down. Patients with PD become hypokinetic – they move less. It becomes harder to move. They need more of a will to move in order to initiate movement. In the end stage, patients with PD can become “frozen”.
The primary treatment for PD is dopamine or a dopamine agonist. Sinemet, which contains L-dopa, a precursor to dopamine, is one mainstay treatment. The L-dopa gets transported into the brain where it is made into dopamine. These treatments work as long as there are some SNpc neurons left to convert the L-dopa and secrete the dopamine. There are also drugs that enhance dopamine function or are direct dopamine agonists. Other drugs are cholinergic inhibitors, as acetylcholine tends to oppose the action of dopamine in the basal ganglia circuits. These drugs all have side effects because dopamine and acetylcholine are used elsewhere in the brain. Also, without the SNpc neurons to buffer the dopamine, end-stage patients with PD go through highly variable symptoms based upon the moment-to-moment drug levels in their blood. They become hyperkinetic, then have a brief sweet-spot, and then hypokinetic, and then repeat that cycle with the next dose.
The fact that PD is the result of a specific population of neurons making a specific neurotransmitter makes it an attractive target for cell therapy. All we need to do is increase the number of dopamine neurons in the SNpc and that can treat, and even potentially cure, PD. The first cell transplant for PD was in 1987, in Sweden. These were fetal-derived dopamine producing neurons. There treatments were successful, but they are not a cure for PD. The cells release dopamine but they are not connected to the basal ganglia circuitry, so they are not regulating the release of dopamine in a feedback circuit. In essence, therefore, these were just a drug-delivery system. At best they produced the same effect as best pre-operative medication management. In fact, the treatment only works in patients who respond to L-dopa given orally. The transplants just replace the need for medication, and make it easier to maintain a high level of control.
They also have a lot of challenges. How long do the transplanted cells survive in the brain? What are the risks of the surgery. Is immunosuppressive treatment needed. And where do we get the cells from. The only source that worked was human ventral mesencephalic dopamine neurons from recent voluntary abortions. This limited the supply, and also created regulatory issues, being banned at various times. Attempts at using animal derived cells failed, as did using adrenal cells from the patient.
Therefore, when the technology developed to produce stem cells from the patient’s own cells, it was inevitable that this would be tried in PD. These are typically fibroblasts that are altered to turn them into pluripotent stem cells, which are then induced to form into dopamine producing neurons. This eliminates the need for immunosuppression, and avoid any ethical or legal issues with harvesting. PD would seem like the low hanging fruit for autologous stem cell therapy.
But – it has run up against the issues that we have generally encountered with this technology, which is why you may have first heard of this idea in the early 2000s and here in 2025 we are just seeing a phase I clinical trial. One problem is getting the cells to survive for long enough to make the whole procedure worthwhile. The cells not only need to survive, they need to thrive, and to produce dopamine. This part we can do, and while this remains an issue for any new therapy, this is generally not the limiting factor.
Of greater concern is how to keep the cells from thriving too much – from forming a tumor. There is a reason our bodies are not already flush with stem cells, ready to repair any damage, rejuvenate any effects of aging, and replace any exhausted cells. It’s because they tend to form tumors and cancer. So we have just as many stem cells as we need, and no more. What we “need” is an evolutionary calculation, and not what we might desire. Our experience with stem cell therapy has taught us the wisdom of evolution – stem cells are a double-edged sword.
Finally, it is especially difficult to get stem cells in the brain to make meaningful connections and participate in brain circuitry. I just attended a grand round on stem cells for stroke, and there they are having the same issue. However, stem cells can still be helpful, because they can improve the local environment, allowing native neurons to survive and function better. With PD we are again back to – the stem cells are a great dopamine delivery system, but they don’t fix the broken circuitry.
There is still the hope (but it is mainly a hope at this point) that we will be able to get these stem cells to actually replace lost brain cells, but we have not achieved that goal yet. Some researchers I have spoken to have given up on that approach. They are focusing on using stem cells as a therapy, not a cure – as a way to deliver treatments and improve the environment, to support neurons and brain function, but without the plan to replace neurons in functional circuits.
But the allure of curing neurological disease by transplanting new neurons into the brain to actually fix brain circuits is simply too great to give up entirely. Research will continue to push in this direction (and you can be sure that every mainstream news report about this research will focus on this potential of the treatment). We may just need some basic science breakthrough to figure out how to get stem cells to make meaningful connections, and breakthroughs are hard to predict. We had hoped they would just do it automatically, but apparently they don’t. In the meantime, stem cells are still a very useful treatment modality, just more for support than replacement.