Parkinson’s disease (PD) is caused by decreased levels of dopamine, a chemical produced in the brain responsible for maintaining smooth movement and motor control, as well as influencing memory, feelings of pleasure, and motivation. In PD, a progressive loss of dopamine-producing cells can cause a range of motor and non-motor symptoms experienced by people living with PD, significantly impacting an individual’s quality of life, relationships, and ability to perform certain functions. By the time a person gets an official PD diagnosis, it is estimated that they have already lost about half of their dopamine neurons.

Current medications for Parkinson’s typically include symptomatic treatments that focus on alleviating motor symptoms (such as tremors) by giving artificial forms of dopamine (e.g., levodopa). However, disease-modifying treatments that focus on halting progression and fixing the root cause of the disease are currently lacking. Recently, treatments that harness the power of stem cells have been in the spotlight for their innovative and promising approaches to replace and restore those dopamine neurons that are progressively lost in the brains of people living with Parkinson’s.

What are stem cells?

Stem cells can be thought of as the universal cell or building blocks of our organs. They are the cells that branch out and become all other cells including brain, skin and muscle cells. Recently, researchers have begun to focus on stem cells, as a potential way to replace the damaged or lost dopamine-producing cells.

There are different sources of stem cells including: adult, embryonic, and induced pluripotent stem cells (iPSCs). Adult stem cells are found all over the body, where they are constantly acting to replace lost or damaged cells. It’s even been estimated that our adult stem cells regenerate and replace 330 billion cells in our body every day (roughly 1% of all cells in the body)¹. However, adult stem cells are restricted and can only replace cell types from the organ where they normally reside, and the stem cells in our brain are not active enough to replace the cells that are damaged in Parkinson’s.

On the other hand, embryonic stem cells (ESCs) can generate any cell type in the entire human body (including brain cells) making them an interesting tool for therapeutic research. ESCs that are used for research come from embryonic tissues that are left unused from in vitro fertilization (IVF) procedures (and are usually destroyed). There are ethical considerations and extensive governmental regulations that must be met before these cells can be used in research to ensure proper safety and ethical sourcing².

Induced pluripotent stem cells (iPSCs) are stem cells that are created in the lab, by taking commonly available cells (such as skin cells) from human tissue and turning them back into a stem cell state. These iPSCs can then be used to generate any cell type (such as dopamine-producing cells) and transplanted back into the body. Since there is the potential to use the patient’s own cells to generate the iPSCs, there could be a smaller risk of rejection for the transplanted cells.

Stem cell therapy for Parkinson’s

For years researchers have been working to design an effective stem cell therapy for Parkinson’s, on the basis that they can potentially create new and functional dopamine-producing cells to replace the cells that are lost or damaged in Parkinson’s³. Parkinson Canada continues to fund groundbreaking research in all therapeutic areas, including stem cells, such as a project led by Dr. Tiago Cardoso at Université Laval who worked on genetic engineering of stem cells to improve cell survival and circuit formation of transplanted cells⁴.

Some groups have developed therapies that use ESCs to generate dopamine precursor cells in the lab that will safely engraft and function in the same way as the dopamine-producing cells that were originally lost in Parkinson’s-affected brains. Due to the abilities of ESCs to self-renew and divide in the lab, they are posing a promising source of stem cells for therapeutic purposes, since every patient that is treated requires several million transplanted cells. This method allows for the production of large-scale batches of dopamine-producing cells that can be tested in animal models to ensure the cells are safe before they are used in human clinical trials³.

Several other groups have taken an approach that starts with either healthy adult donor cells (allogenic) or an individual’s own skin cells (autologous).  These iPSC-based approaches also generate dopamine precursor cells which will be transplanted into the brains of Parkinson’s patients. However, due to the personalized nature of using patient-specific iPSCs, the process can be much more laborious, time-consuming and expensive, with some estimates putting the cost of treating one patient at $800,000 ^{3, 5}.

Two major risks of any cell transplantation therapy are: 1) the potential for tumor formation from cells that still retain stem cell-like characteristics, and 2) rejection of the transplanted cells. Therefore, before any cells are transplanted into patients, researchers implement rigorous methods in the lab that ensure the cells used for transplantation are a pure population of dopamine precursor cells. To prevent rejection of transplanted cells, many groups include the use of immunosuppressive drugs for at least 12 months³. Interestingly, transplants that use the patient’s own cells as the starting material don’t need to use these immunosuppressive drugs, as was successfully shown in a clinical research study from Harvard University in one Parkinson’s patient⁶.

Early clinical trial results show promise

BlueRock Therapeutics recently presented the results from a phase I clinical trial, in which 12 Parkinson’s patients in Canada and the United States received a surgical transplantation of either a low dose (1.8 million cells) or high dose (5.4 million cells) of the stem cell derived therapy called bemdaneprocel. These patients were followed for 1 year to evaluate overall safety, tolerability and improvements towards motor symptoms. These patients will continue to be followed for an additional year.

Importantly, over the 1-year follow-up period, it was reported that none of the patients had any serious adverse events related to the therapeutic. Imaging scans (used to visualize and assess dopamine activity) also showed that the transplanted dopamine cells were surviving and successfully engrafting in the patients’ brains. This means that the clinical trial achieved its primary goal of showing safety and tolerability of the treatment in Parkinson’s patients⁷.

Patients were also evaluated for improvements to their motor symptoms, and in both the low and high dose groups there were improvements, with more time spent in the “ON” state (symptoms are well controlled) and less time spent in the “OFF” state (symptoms are worsened). Patients who received the higher dose showed the greatest improvements on clinical monitoring scales.

The STEM-PD group has also begun their Phase 1/2 clinical trial in Sweden. They plan to perform cell transplantation surgeries on 8 patients with moderately advanced Parkinson’s. First, 4 patients will be injected with the low dose (7 million cells) and monitored for 6-10 months for safety before performing injections in the second group of 4 high dose patients (14.2 million cells). Patients will be followed for 12 months to assess the safety and tolerability of the two dosages, and evaluation will continue for 3 years to fully evaluate how effective this treatment is at reducing clinical motor symptoms such as time spent in the “OFF” state^8-9.

The CiRA group in Kyoto (Japan) has also begun their Phase 1/2 clinical trial, with the goal of testing their iPSC-based stem cell therapy in 7 Parkinson’s patients. They plan to follow each patient for 2 years to evaluate safety and tolerability. Results from this study are expected to be released in 2024^10-11.

Finally, Aspen Neuroscience recently received FDA clearance to proceed with clinical trials of a treatment that will take skin cells from individual Parkinson’s patients to generate iPSCs and then grow millions of dopamine-producing cells for transplantation back into the patient’s own brain. To date, the company hasn’t released any detailed information on the number of patients to be dosed or the timing for publishing results from their upcoming trial¹².

It is important to note that stem cell transplantation approaches are still experimental, and none have been approved by Health Canada or the FDA for widescale use in PD. It is recommended that people living with Parkinson’s be cautious of any group that is selling a cell transplantation product or surgery for Parkinson’s that is not associated with an approved clinical trial, and to discuss these treatments further with their medical team.

It is encouraging to see advancements in the field of dopamine cell replacement therapies and we look forward to seeing the results from more advanced Phase 2 and Phase 3 results from these groups in the future. These larger scale clinical trials are crucial to provide further evidence on the safety and efficacy of any potential therapeutic.

References

1. Our Bodies Replace Billions of Cells Every Day – Scientific American
2. Stem Cells: What’s the latest?. We discuss the latest research… | by Rachel Lesbirel | Parkinson’s UK | Medium
3. Cha, Y. et al., (2023). Current Status and Future Perspectives on Stem Cell-Based Therapies for Parkinson’s Disease. J Mov Disor. 16(1):22-41 – link to paper
4. Modifying stem cells to treat Parkinson’s – Parkinson Canada
5. Doss and Sachinidis. (2019). Current Challenges of iPSC-Based Disease Modeling and Therapeutic Implications. Cells. 8(5); 403 – link to paper
6. Schweitzer, J.S., et al., (2020). Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson’s Disease. New Eng. J. Med. 382: 1926-1932 – link to paper
7. BlueRock’s Phase I study with bemdaneprocel in patients with Parkinson’s disease meets primary endpoint – BlueRock Therapeutics LP (bluerocktx.com)
8. Kirkeby, A. et al., (2023). Preclinical quality, safety, and efficacy of a human embryonic stem cell-derived product for the treatment of Parkinson’s disease, STEM-PD. Cell Stem Cell. 30(10): P1299-1314. – link to paper
9. The STEM-PD Clinical Trial
10. The Bluerockers have started – Cure Parkinson’s (cureparkinsons.org.uk)
11. CiRA Annual Report 2022 (kyoto-u.ac.jp)
12. Aspen Neuroscience