Dopamine Cell Replacement Therapy: A New Frontier in Parkinson Disease Treatment

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Dopamine Cell Replacement Therapy: A New Frontier in Parkinson Disease Treatment

Dopaminergic cell replacement therapy is re-emerging as an investigational strategy for Parkinson disease (PD), supported by a growing number of early-phase clinical trials reporting favorable preliminary safety findings and early motor improvements.1

Evolution of Dopamine Cell Replacement in PD

Early efforts to replace dopaminergic neurons in PD began in the 1980s, but were limited by several challenges.1

“Initial human fetal ventral mesencephalon cell transplantation showed some encouraging results with graft survival and striatal dopamine synthesis,” said Jacob Yomtoob, MD, a movement disorders fellow at Northwestern Feinberg School of Medicine in Chicago, Illinois, and co-author of a 2026 review describing cell therapies and other advanced therapeutics in PD.2

 

When [pluripotent stem cell] technology became accessible, it was almost a no-brainer to develop strategies to derive dopaminergic neurons in the lab with a plan to eventually implant them in the brain.

“However, concerns arose about variable efficacy and graft-induced dyskinesias, and there were also significant supply concerns regarding sourcing fetal stem cells,” Dr Yomtoob continued.

More recently, the open-label TransEuro trial failed to show improvement in the primary outcome – the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III OFF score – at 36 months among patients with PD who were treated with human fetal ventral mesencephalic transplantation.3

Those results “largely confirmed the limitations and highlighted the need for alternative pluripotent stem cell sources informed by decades of laboratory studies and in-human trials,” Dr Yomtoob noted.

Together, these limitations have driven a shift toward stem cell-based strategies as a more scalable and standardized approach to dopaminergic replacement.

With advances in cell technology, it is now feasible to generate dopaminergic progenitor cells from sources such as human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs), and parthenogenetic stem cells (hpSCs), Dr Yomtoob explained.2

“When [pluripotent stem cell] technology became accessible, it was almost a no-brainer to develop strategies to derive dopaminergic neurons in the lab with a plan to eventually implant them in the brain,” said Viviane Tabar, MD, chair of the department of neurosurgery and the Theresa Feng Chair in Neurosurgical Oncology at Memorial Sloan Kettering Cancer Center in New York, New York.

Dr Tabar cited multiple advantages of pluripotent stem cells (PSCs) compared with fetal stem cells. “They can be expanded on a large scale, and they can be directed to differentiate into very specific neuron types,” she said.1 “Importantly, it was possible to direct differentiation of PSC into authentic midbrain neurons with no serotonergic neuron contamination.”

Serotonergic neurons may have been the cause of dyskinesia in those earlier trials of fetal tissue grafts in PD, Dr Tabar noted.

Among other benefits, PSC-derived products “can be subjected to rigorous quality assurance testing to make sure they have the correct phenotype and are devoid of unwanted contaminants,” Dr Tabar added.1

Building on this preclinical and translational rationale, several early-phase clinical trials have now begun evaluating PSC–derived dopaminergic progenitors in patients with PD.

Recent Early-Phase Trials

In an open-label phase 1 clinical trial (ClinicalTrials.gov Identifier: NCT04802733) published in Nature in May 2025, Dr Tabar and colleagues assessed the safety and tolerability of bilateral putaminal transplantation of a cryopreserved, off-the-shelf hESC-derived dopaminergic neuron progenitor cell product (bemdaneprocel) in 12 patients with PD. Participants were sequentially enrolled in low-dose and high-dose cohorts.4

The trial met its primary endpoints of safety and tolerability at 12 months, and no cases of graft-induced dyskinesia were observed. In addition, no adverse events (AEs) related to the cell product were reported.

Dr Tabar noted that, at 18 months, the data showed continued safety and “no serious adverse events, including no dyskinesias and no tumor formation.”

Among the trial’s secondary endpoints, the MDS-UPDRS Part III OFF scores demonstrated a mean improvement of 8.6 points in the low-dose cohort and 23.0 points in the high-dose cohort. This change is “consistent with a moderate and large ‘clinically important difference’ in motor score,” the authors wrote.4

Additional clinical evidence is emerging from parallel phase 1 and 2 studies using alternative pluripotent stem cell-derived products and manufacturing approaches.

In an open-label dose-escalation phase 1/2a trial (ClinicalTrials.gov Identifier: NCT05887466) published in Cell in December 2025, investigators in Korea evaluated the safety and exploratory efficacy of bilateral putaminal transplantation of freshly cultured hESC-derived dopaminergic progenitors (A9 subtype) among 12 patients with PD. This trial also included a low-dose and a high-dose cohort.5

The study met its primary endpoints at 12 months, with no observed dose-limiting toxicities or graft-related AEs. Exploratory outcomes showed greater MDS-UPDRS Part III OFF score improvements in the high-dose group compared with the low-dose group (15.5 vs 12.7), along with improvements in activities of daily living, motor function, and quality of life.5

Further, a phase 1/2 trial in Japan evaluated bilateral putaminal transplantation of freshly cultured iPSC-derived dopaminergic progenitor cells in 7 patients with PD. The study reported no serious adverse events or graft overgrowth, with mean improvements of 9.5 points in MDS-UPDRS Part III OFF scores and 4.3 points in ON scores.6

Currently, a phase 1 multisite, open-label trial (ClinicalTrials.gov Identifier: NCT06687837)is evaluating autologous iPSC-derived dopaminergic progenitor cells in 12 patients with PD in the United States.7 Xenos Mason, MD, a co-principal investigator on the study and neurologist at Keck Medicine at the University of Southern California in Los Angeles, explained that his team is “conducting studies using neuroimaging and wearable sensors to understand, for example, how stem cells integrate into brain circuits.” Dr Mason added that these methods may elucidate “how the presence of these cells and the dopamine that they produce modifies the intrinsic neurophysiology and the pathophysiology of different forms of [PD].”

Future Directions

As early clinical data continue to accumulate, attention is now shifting toward larger confirmatory trials and longer-term outcome assessment.

The future trajectory of dopamine cell replacement therapy in PD will become more defined in the coming years as larger trials continue to test this approach, according to Dr Tabar.

In addition to ongoing early-phase studies, a phase 3 randomized sham surgery-controlled trial (ClinicalTrials.gov Identifier: NCT06944522) of bemdaneprocel is being conducted at Memorial Sloan Kettering Cancer Center and other sites.

“With more patients receiving the treatment, we expect to learn a lot more about the profile of those who benefit the most, so the indications will become more refined with growing input from patients and their neurologists,” Dr Tabar stated.

While the optimal timing for dopamine cell replacement therapy in the course of PD remains to be determined, Dr Mason suggested some possibilities: “If we think of stem cells as analogous to other procedural therapies for PD, it may be best to use them when medications start to lose efficacy, which tends to occur 3 to 10 years into the course of the disease.”

“However, it may be that stem cells offer a very safe and durable symptomatic improvement, in which case it may be most appropriate to offer the therapy earlier – perhaps soon after diagnostic confirmation,” Dr Mason continued.

According to Dr Yomtoob, dopamine cell replacement therapies in PD will initially be compared with deep brain stimulation (DBS) and magnetic resonance imaging-guided focused ultrasound. “Time will tell if cell therapies have proven benefits over DBS – such as potential for slowing or delaying disease progression and no need for an implanted device or battery replacement – that overcome downsides such as the need for immunosuppression with most dopamine cell therapies, a lack of adjustability over time, and the risk [for] graft-induced side effects.”

Along with long-term safety and efficacy and identification of the optimal patient population, additional questions to be resolved in ongoing research include the optimal dopaminergic progenitor cell source, the need for immunosuppression, and the role of these therapies in the PD treatment landscape, Dr Yomtoob said.

Dr Tabar and other scientists are continuing to explore ideas regarding future versions of cell products, including “development of a better specified dopaminergic neuron subtype, methods to improve graft survival, variations on where exactly in the brain the cells should be grafted, the design of better devices for delivery of the cells, and the possibility of combining cell therapy with novel small molecules or other approaches such as genetically modified cells that impact disease progression or are more resistant to the disease,” she explained.

“Importantly, the success of cell therapy in PD will open the door for similar strategies for other CNS disorders,” Dr Tabar said.