Cell therapies hold great promise to treat Parkinson’s disease, but there’s an ongoing debate over how to best do this. One group—and I am firmly in this camp—maintains an autologous therapy, derived from a patient’s own cells, is the correct path. Others believe an allogeneic approach, using donor cells, would be more cost-effective.
A recent study, published in the New England Journal of Medicine, added fuel to the fire. A research team, led by Harvard’s Kwang-Soo Kim, PhD, harvested cells from a person suffering from Parkinson’s disease, created induced pluripotent stem cells (iPSCs) and differentiated them into dopamine-producing neurons, which were ultimately transplanted into that person’s brain.
While this work generated some controversy, the procedure was well-tolerated for the study’s only participant, and that’s a first step towards establishing a safe track record for autologous neuronal cell transplants.
This narrow proof-of-concept will do little to settle the ongoing debate between allogeneic and autologous transplants. However, as the discussion moves forward, we must carefully assess all the evidence. This choice is an important inflection point for people with Parkinson’s disease—we need to make the right decisions based on the best, currently available data.
Autologous vs. allogeneic
Given the evidence, autologous therapies offer the most compelling opportunities to treat Parkinson’s disease, and give patients better quality of life, because they do not precipitate an immune response. Since allogeneic cells come from a donor and not from the person being treated, they are like heart, lung or kidney transplants: Recipients must take immunosuppressive drugs for their grafts to survive.
The jury is still out on which immunosuppressive regimens will be needed to protect allogeneic transplants from the immune system and how long those will be needed. Immunosuppression has a dramatic impact on quality of life, making people more vulnerable to opportunistic infections. The COVID-19 pandemic is an ongoing reminder that being immunosuppressed, for any amount of time, can be quite dangerous.
Since autologous transplants are generated from a person’s own cells, they will not need any immunosuppression, and that would be a big win for patients.
There’s also evidence that autologous neurons create synapses more efficiently. Presynaptic axons must scan their environments to make the appropriate connections with dendrites from other neurons. They perform this feat with such accuracy that many researchers believe axons and dendrites are encoded in some way to make those correct connections.
Alternatively, dopaminergic and other neurons can form autapses, in which they connect to themselves rather than targeting the right neurons. Though we do not fully understand how this mechanism works, we do know that neurons from autologous transplants share the same coding with their neighbors. As a result, they appear to reject autapses, favoring synapses and generating optimal connections to produce functional circuits. This may seem like a subtle detail, but it’s critically important if we want to restore function in Parkinson’s disease patients.
Another potential issue is redosing. We don’t know how long any cell transplant–autologous or allogeneic—will benefit certain patients. Parkinson patients with the sporadic (non-familial) form of the disease can start developing symptoms before they turn 50. As a result, they may need a second, or possibly even a third, transplant procedure to manage their disease.
This is an important consideration when choosing which path is the best choice for patients. If they have received an allogeneic transplant, that original cell line will have become immunogenic. However, patients who benefit from autologous transplants can continue to receive their own cells without any concerns over immunogenicity. For patients who need additional dopamine-producing neurons down the road, autologous cells are clearly the better option.
Making the fine distinctions
When assessing autologous and allogeneic transplants, we must recognize that there is significant diversity in these methods, and the scientific community should not treat them as two monolithic approaches.
For example, researchers can adopt various methods to convert mature cells into iPSCs and differentiate them into dopaminergic neurons for transplant. Kwang-Soo Kim’s group used a flavanol to destroy senescent cells during the differentiation process. This added another step that exposes transplant cells to a chemical, and that may not be the best way to proceed.
There are also different types of Parkinson’s disease, and treatments should reflect that diversity. Patients with sporadic Parkinson can receive transplanted dopaminergic neurons without any additional molecular interventions.
Patients with familial Parkinson’s disease, such as those who have mutations in their GBA gene, may be better served by autologous neuronal transplants that also deliver gene therapy. Providing patients with healthy genes, which produce appropriate amounts of the GBA enzyme, could go a long way towards restoring function.
These are just a couple examples of how complex it can be to develop cell therapies for Parkinson’s disease. This complexity should always be taken into account when assessing new therapies; apples should always be compared to apples.
Calculating cost and value
Sophisticated therapies and cost concerns often go together. On the surface, allogeneic neuron transplants would project as being less expensive than autologous therapies. Because a given cell line could serve a relatively large population of affected people, manufacturing costs could be reduced. However, there are other variables to consider.
While it’s true allogeneic lines could be scaled up effectively, there are risks associated with higher volumes. Larger scale can translate into greater risks of generating mutations in these cell lines. Some of these mutations could activate oncogenes.
Manufacturers would have to invest in elaborate quality control measures to protect patients, and that would add significant costs to the overall process.
Immunosuppression would also be costly. These drugs are expensive, and no one currently can say how long people will need them. Being vulnerable to infection generates other issues. For high-risk transplant patients, routine viral infections could lead to precautionary hospitalizations, as well as outpatient visits. For others, health-related complications from immunosuppression could lead to lengthy, expensive hospitalizations. The longer people need immunosuppression, the greater their risk.
We must also remember that cost projections to produce autologous neurons are moving targets, and they have a tendency to move lower. As we perfect iPSC protocols, and transfer those approaches from the lab to manufacturing, we will continue to automate processes and identify other efficiencies. By implementing the most innovative manufacturing protocols, companies can significantly reduce the cost of producing autologous neurons.
If we factor in all these expenses, the cost advantages associated with allogeneic transplants tend to dissipate. Still, costs are not exclusively a monetary realm. Some have expressed concerns that producing neurons for autologous transplant will take too long, and patients may decline precipitously while waiting.
This is actually a red herring. Mature cells can be converted into iPSCs and subsequently differentiated into dopaminergic neurons in less than four months. During that short period, it’s unlikely that a Parkinson patient eligible for this type of therapy would experience any clinically-detectable deterioration.
We still have a long way to go with cell therapies. To move forward with autologous neuron transplants, we need to approach them in a rigorous and systematic way, conduct robust, well-designed clinical trials to study safety, tolerability and efficacy and develop innovative neurosurgical approaches.
Howard Federoff, MD, PhD, is CEO at Aspen Neuroscience.