A New Era in Regenerative Medicine: Cell Replacement Therapy for Parkinson’s Disease Is on the Horizon

Parkinson’s disease (PD), characterized by the selective loss of midbrain dopaminergic neurons (mDANs), is a promising target for cell replacement therapy. Two recent clinical trials^1,2 published in Nature report the safety and potential efficacy of human pluripotent stem cell-based approaches, representing a major milestone in regenerative medicine for PD.

Regenerative medicine (RM) aims to restore normal physiological function by repairing or replacing damaged cells, tissues, or organs. Among RM strategies, organ transplantation remains one of the most successful and transformative. Although the concept dates back centuries, a major breakthrough occurred in 1954, when Dr. Joseph Murray performed the first successful kidney transplant between identical twins.³ In 2023 alone, over 172,000 organ transplants were performed globally (https://www.transplant-observatory.org/), providing life-saving treatments for end-stage organ failure. However, the persistent shortage of donor organs underscores the urgent need for alternatives. The advent of human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), has revolutionized RM by offering cells with unlimited self-renewal and pluripotent differentiation potential, opening unprecedented opportunities to develop stem cell-based therapies and usher in the next generation of RM.

Parkinson’s disease (PD), the most common neurodegenerative movement disorder, affects ~1% of individuals over the age of 60. Its hallmark pathology – the selective degeneration of midbrain dopaminergic neurons (mDANs) – makes it an ideal target for cell replacement therapy (CRT). Early fetal cell transplantation trials in the 1980s-1990s provided critical proof of concept but faced significant issues, including graft-induced dyskinesia (GID)⁴. Over the past two decades, advances in hPSC technology have enabled the development of CRT platforms, leading to PD clinical trials initiated in countries including Australia, Canada, China, Iran, Israel, Japan, Korea, Sweden, the United Kingdom, and the United States.⁵ The first hPSC-based CRT in PD was reported in 2020 under FDA expanded access, using autologous mDA progenitors (mDAPs) transplanted without immunosuppression.⁶ The two newly published trials using allogeneic hiPSC- and hESC-derived mDAPs mark another milestone toward clinical translation (Table 1).^1,2

Table 1.

Comparison of three hPSC-based clinical trials of PD.

	Sawamoto et al. 1	Tabar et al. 2	Schweitzer et al. 6
Cell source	allogeneic hiPSC-derived mDAPs	allogeneic hESC-derived mDAPs (bemdaneprocel)	autologous hiPSC-derived mDAPs
Final cell product	fresh mDAPs harvested on day 30 (sorted using Corin-antibody)	cryopreserved mDAPs harvested on day 16	fresh mDAPs harvested on day 28
Cell purity	~60% mDAPs + ~40% mDANs	primarily mDAPs (not explicitly stated)	~90% mDAPs + ~10% mDANs
Genomic stability	WGS, karyotyping (pre-clinical paper)	karyotyping	WGS/WES, karyotyping
Number of patients	7 total: low dose (n=3); high dose (n=4)	12 total: low dose (n=5); high dose (n=7)	1
Cell dose	low: 2.1~2.6M per side; high: 5.3~5.5M per side	low: 0.9M per side; high: 2.7M per side	4M per side
Follow-up duration	24 months	18 months	24 months
Imaging and biomarker assessment	MRI (graft size, tumor monitoring) 18F-DOPA PET (graft survival/function) 18F-GE180 PET (inflammation) 18F-FLT PET (cell proliferation)	MRI (graft size, tumor monitoring) 18F-DOPA PET (graft survival/function)	MRI (graft size, tumor monitoring), 18F-DOPA PET (graft survival/function)
Primary outcome (safety)	no tumor or abnormal outgrowth no GID	no tumor or abnormal outgrowth no GID	no tumor or abnormal outgrowth no GID
Secondary outcome (efficacy)	MDS-UPDRS III OFF MDS-UPDRS III ON PDQ-39 scores Hoehn-Yahr stage 18F-DOPA PET Ki LEDD	MDS-UPDRS III OFF MDS-UPDRS III ON PDQ-39 scores Hoehn-Yahr stage LEDD	MDS-UPDRS III OFF MDS-UPDRS III ON PDQ-39 scores Hoehn-Yahr stage LEDD
Immunosuppression	tacrolimus for 15 months	tacrolimus, prednisone, and basiliximab for 12 months	none

Abbreviation: WGS, whole-genome sequencing; WES, whole-exome sequencing; M, million; MRI, magnetic resonance imaging; ¹⁸F-DOPA, fluorine-18-dihydroxyphenylalanine; ¹⁸F-GE180, fluorine-18-flutriciclamide; ¹⁸F-FLT, fluorine-18-fluorothymidine; PET, positron emission tomography; MDS-UPDRS III, Movement Disorder Society-Unified Parkinson’s Disease Rating Scale part III; PDQ-39, 39-item Parkinson’s Disease Questionnaire; LEDD, levodopa equivalent daily dose.

In the Sawamoto et al. study, a clinical-grade hiPSC line (QHJI01s04), derived from a healthy donor homozygous for Japan’s most common human leukocyte antigen (HLA) haplotype (~17% frequency), was used to reduce immunogenicity. Cells were differentiated for 11–13 days, sorted via CORIN-based selection to eliminate non-target cells, and cultured until day 30. The final cell product consisted of ~60% mDAPs and ~40% mDANs. Seven sporadic PD patients received transplants – three at low-dose and four at high-dose. Tacrolimus immunosuppression was administered, halved at 12 months, and discontinued at 15 months. No serious adverse events or GID were observed over 2 years. Of six evaluable patients, four improved in Movement Disorder Society-Unified Parkinson’s Disease Rating Scale part III (MDS-UPDRS Part III) OFF scores (mean reduction, 9.5 points), five improved in ON scores (mean reduction, 3.1 points), and four improved in Hoehn–Yahr staging. Parkinson’s Disease Questionnaire (PDQ-39) quality-of-life scores showed no significant change. These findings differ from the first autologous case, where the patient showed robust PDQ-39 improvement but only modest motor benefit.⁶ In a parallel phase 1 open-label trial, Tabar et al. used hESC-derived mDAPs (bemdaneprocel), produced under good manufacturing practice (GMP) conditions for 16 days and cryopreserved for large-scale, off-the-shelf use. Twelve patients were divided into low-dose (n = 5) and high-dose (n = 7) cohorts. Standard immunosuppression for solid organ transplantation was administered for 12 months and then discontinued. No serious adverse events or GID occurred. Mean MDS-UPDRS Part III OFF scores improved by 8.6 points in the low-dose and 23 points in the high-dose group, indicating dose-dependent effects. Greater improvements in MDS-UPDRS Part II and PDQ-39 scores were also observed in the high-dose cohort. In both studies, fluorine-18-dihydroxyphenylalanine (¹⁸F-DOPA) positron emission tomography (PET) imaging confirmed graft survival and dopaminergic activity via increased putaminal uptake, even after immunosuppression withdrawal.

These early trials collectively support the feasibility, initial safety, and potential efficacy of hPSC-based CRT for PD (Table 1). Together with the lack of tumor formation, the absence of GID, a complication that plagued fetal cell trials, is particularly encouraging.⁴ Still, the findings warrant cautious interpretation, given the open-label designs, small cohorts, limited statistical power, and relatively short follow-up. Ongoing trials, including three autologous approaches,⁵ will further define the therapeutic landscape. The history of organ transplantation offers valuable lessons, showing how decades of iterative setbacks and refinements were required to overcome major barriers before transplantation became standard therapy.³ Equally important – and perhaps more directly relevant to CRT – are the lessons from fetal cell transplantation, which, despite early enthusiasm, faced significant practical, medical, and ethical concerns.⁴ Notably, the European Union funded a new open-label trial called TransEuro in 2010, with the goal of optimizing fetal cell transplantation and developing it into a routine therapeutic strategy. This major clinical effort, conducted by multiple investigators at two surgical sites (Cambridge, United Kingdom and Lund, Sweden), was recently completed and published. The study, involving 27 PD patients in total (11 transplanted and 16 control), found no overall clinical benefit at 3 years post-grafting when compared with either baseline measures or the nongrafted natural history control group.⁷ Although this trial provides valuable insights to inform the future development of hPSC-based CRT, it also underscores the persistent – and likely insurmountable – logistical barriers associated with fetal cell transplantation.

Building on these precedents, we propose the following key considerations and recommendations:

First, though no serious adverse events were observed, long-term safety remains uncertain. GID, though absent, remains incompletely understood and warrants continued monitoring. The inherent pluripotency of hPSCs poses a teratoma risk if even a small number of undifferentiated cells persist. Extended culture can lead to oncogenic mutations.⁸ Periodic genomic surveillance of hPSC lines and final products should be standard practice. The history of gene therapy illustrates how isolated adverse events can profoundly delay progress.

Second, robust, sustained efficacy is a central goal. Although fetal cell transplantation is no longer pursued, some patients experienced decade-long benefits, including reduced medication needs. Whether hPSC-based CRT can achieve similar outcomes remains to be seen. This will require a deeper understanding of transplantation biology and systematic optimization of both in vitro and in vivo parameters. A particular challenge lies in the developmental and pathological environment that transplanted cells will encounter because the PD brain lacks the complex spatiotemporal developmental cues, including signaling molecules and transcription factors, that guide the maturation into fully functional mDANs in the embryonic brain. In addition, the pathological milieu of the PD brain, marked by chronic neuroinflammation, oxidative stress, and alpha-synuclein pathology may further impede neuronal survival, maturation, and functional integration. Presently, fewer than 3% of grafted mDAPs mature into functional mDANs. Thus, developing strategies to enhance graft survival, phenotypic maturation, and integration remains a critical priority.

Third, immune challenges remain formidable. Although autologous hiPSC-derived cells may escape adaptive immune rejection, allogeneic cells require immunosuppression. Moreover, surgical injury can activate innate immune responses, causing acute loss of grafted mDANs in both autologous and allogeneic settings. Our group recently showed that over 90% of grafted hPSC-derived mDANs died within 2 weeks due to innate immune activation.⁹ Addressing both adaptive and innate immunity is critical. It is plausible that similar immune mechanisms contributed to variable and inefficient outcomes in fetal cell transplantation, ultimately limiting its adoption.

Finally, donor- and recipient-level variability is an emerging challenge. Despite identical cell preparation, patients showed variable responses in both trials. Should non-responders undergo a second transplant? Notably, in a recent preclinical study, mDAPs from one PD patient’s hiPSC line failed to improve motor function in animal models,¹⁰ highlighting donor-intrinsic variability. Understanding how inter-individual variabilities, disease stage, and host environment influence therapeutic efficacy will be key to optimizing CRT.

In conclusion, the two recent Nature papers mark a pivotal step forward for hPSC-based RM and signal real momentum for CRT in PD. Though the promise is real, much work remains. Based on these promising advances and with interdisciplinary collaboration, innovation, and iterative refinements, we are cautiously optimistic that hPSC-based CRT will become a transformative therapeutic option for PD in the foreseeable future.