Human embryonic stem cell-derived dopaminergic cells for Parkinson’s disease: a phase 1/2 open-label trial

Parkinson’s disease (PD) is characterized by progressive loss of nigral dopaminergic neurons, resulting in disabling motor symptoms. Intracerebral transplantation of stem cell-derived dopaminergic progenitors to replace lost endogenous dopaminergic neurons offers a new potentially restorative therapeutic approach for PD. Here we report the 12-month primary safety end point and interim efficacy outcomes from a phase 1/2, open-label, multicenter trial evaluating STEM-PD, a cryopreserved, off-the-shelf dopaminergic progenitor product derived from human pluripotent stem cells. Eight individuals with moderate PD underwent bilateral intraputaminal transplantation at two escalating doses ( n = 4 per cohort), followed by 12 months of immunosuppression. Seven participants completed 12-month follow-up; one participant died from a pulmonary infection. No serious adverse events were attributed to the cell product, no graft-induced dyskinesias were observed and serial magnetic resonance imaging showed no evidence of tumor formation. These findings support the feasibility and favorable safety profile of human pluripotent stem cell-derived dopaminergic progenitor transplantation in this early-phase study, with risks primarily associated with the immunosuppression regimen. Ongoing follow-up to 36 months will further evaluate durability, clinical outcomes and graft function. ClinicalTrials.gov identifier: NCT05635409 .

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. Neurological conditions are currently the leading global cause of disability, with PD being the fastest growing among them in terms of prevalence, disability-adjusted life years and mortality rates 1 . As of 2019, more than 8.5 million individuals worldwide were estimated to be living with PD, a number projected to exceed 12 million by 2040 2 .

The hallmark pathology of PD involves progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the subsequent loss of their projections to the striatum. This results in striatal dopamine deficiency, which underlies many of the cardinal motor features of the disease: rigidity, bradykinesia and in some cases tremor 3 , 4 . At the time of clinical diagnosis, more than 50% of dopaminergic neurons in the SNpc and over 70% of striatal innervation have typically already been lost 5 .

Current therapies for PD are primarily symptomatic and do not halt disease progression. Pharmacological treatments aim to restore dopaminergic tone using levodopa (L-dopa), dopamine agonists and enzyme inhibitors or to modulate other neurotransmitter systems (for example, amantadine) to counteract some of the motor complications of long-term L-dopa treatment such as L-dopa-induced dyskinesias (LIDs). These treatments, although initially highly effective, become less reliable with disease progression, as patients often develop motor complications, including fluctuations and dyskinesias, as well as nonmotor side effects such as hallucinations 6 . Approximately 10% of PD cases present before the age of 50 years, with many of these individuals expected to live with the disease and the progressively worsening medication side effects for more than two decades.

Device-assisted therapies such as deep brain stimulation (DBS) and magnetic resonance imaging (MRI)-guided focused ultrasound are used to alleviate some of these complications, along with dopaminergic pump therapies 6 , 7 . However, none of these interventions restore the underlying neuronal loss or the dopaminergic transmission back to normal 8 .

Cell-based replacement strategies aim to address this unmet need by reintroducing functional dopaminergic neurons into the striatum. Early clinical trials using human fetal ventral mesencephalic (VM) tissue demonstrated proof of principle: transplanted dopaminergic neurons can survive long term in the host brain 9 and, in some patients, provide durable symptomatic benefit over decades 10 . In these patients, the storage and release of dopamine had been restored to normal levels in grafted striatal areas. However, outcomes have been inconsistent across studies 11 , 12 , 13 and the use of fetal tissue is limited by ethical, logistical and standardization challenges 14 , 15 .

These limitations have catalyzed efforts to develop standardized and scalable dopamine cell therapy products derived from pluripotent stem (PS) cells, including human embryonic stem (ES) cells and induced PS (iPS) cells. Several such products are now in clinical development (see refs. 16 , 17 for review), with early safety and feasibility data emerging 18 , 19 , 20 .

The STEM-PD trial was initiated to evaluate the safety, tolerability and feasibility of intraputaminal transplantation of STEM-PD, a cryopreserved dopaminergic progenitor cell product derived from the clinical-grade human ES cell line RC17 21 , in patients with moderately advanced PD. This 3-year phase 1/2, open-label, multicenter, single-arm, dose-escalation trial was conducted under an advanced therapy investigational medicinal product (ATIMP) framework.

The primary end point of this trial is defined as the number and nature of adverse events (AEs) and serious AEs (SAEs) occurring within the first 12 months following transplantation and the absence of space-occupying lesions on cranial MRI during the same period. Secondary and exploratory outcomes will evaluate the course and efficacy of clinical features, the survival of grafted dopaminergic cells at 36 months as well as additional safety signals occurring between 12 and 36 months and any dose–response effects.

Here, we report the 12-month primary end point safety data and interim efficacy data of the trial.

A total of eight participants were screened (all recruited from the TransEuro observational cohort 15 ) and sequentially enrolled into either the low-dose ( n = 4) or high-dose ( n = 4) cohort. The first participant was enrolled on 3 January 2023 and the last on 13 September 2024. One participant in the high-dose cohort died 10 weeks after transplantation from a fungal pulmonary infection. Safety data from this individual are included through to the time of death. All remaining participants completed the 12-month follow-up and continue to be assessed as part of the trial (Fig. 1a ). Across both dose groups, the median age at baseline was 63 years (range 58–70 years), the median disease duration 14.5 years (range 12–18 years) and six participants (75%) were male (Table 1 ). All patients were graded Hoehn–Yahr stage 2 in the OFF state and none of the participants had LIDs exceeding a score of 2 points in any body part using the Abnormal Involuntary Movement Scale (AIMS) for dyskinesia assessment. The adjusted OFF time was 2 h (range 1–12 h) in the low-dose group and 3 h (range 0–4 h) in the high-dose group (Table 1 ).

a , Participants were enrolled at Skåne University Hospital ( n = 6) and Addenbrooke’s Hospital ( n = 2) between 7 December 2022 and 13 September 2024. The first four participants were allocated to the low dose and the subsequent four to the high dose. One participant in the high-dose group died 10 weeks after transplantation; safety data are reported up to the time of death. Follow-up of the remaining seven participants is ongoing. Transplantations were conducted in a staggered manner with predefined safety intervals. Safety data were reviewed by the Trial Management Group (TMG) and the Data Safety Monitoring Board (DSMB) before each subsequent transplantation and before dose escalation, following review of safety data up to 6 months after transplantation of participant 4. b , Cells were administered along five tracts per hemisphere into the putamen. c , Schedule of safety MRI, [ 18 F]F-DOPA PET and [ 18 F]FE-PE2i PET imaging, immunosuppression and clinical assessments up to the 12-month primary end point.

Three SAE’s occurred in three participants during the 12-month follow-up period and are presented in Table 2 . One patient (low dose) required prolonged hospitalization owing to transient worsening of parkinsonian symptoms and anxiety after transplantation following temporary discontinuation of dopaminergic medication during surgery and in response to anesthesia medications. The symptoms resolved fully over time with reintroduction of the regular dopaminergic therapy. Another participant (high dose) experienced visual hallucinations 5 months after the transplant. This episode followed an adjustment of medications, specifically an increased dose of a dopamine agonist, and occurred in association with a urinary tract infection, necessitating brief hospitalization. The symptoms resolved with medical management and did not return. The third SAE occurred in the patient (high dose) who developed a disseminated pulmonary aspergillosis infection with subsequent central nervous system involvement while on active immunosuppression (azathioprine, tacrolimus and corticosteroids) and died 10 weeks after transplantation despite antifungal medication and withdrawal of immunosuppression. This patient was the second-to-last to undergo transplantation and, at that time, all participants had received a transplant. Only one patient remained on a high-dose steroid taper, and the tapering regimen for this patient was subsequently modified.

None of the SAEs were attributed to the cell product itself or the surgical device. Importantly, no MRI evidence of tumor formation or abnormal tissue growth was observed in any patient during the 12-month follow-up period.

A total of 373 non-serious AEs were reported up to the 12-month end point (194 events in the low-dose and 179 events in the high-dose cohort; Table 3 ). The most frequently reported AEs were laboratory abnormalities (65%), defined in this trial as any deviation from the reference range, irrespective of clinical relevance (Extended Data Table 1 ). AEs occurring after study intervention were predominantly mild (45% low dose; 44% high dose) or moderate in severity and are presented according to their assessed possible relationship to immunosuppression, surgery or the cell product in Table 3 . Importantly, no graft-induced dyskinesias (GIDs) were observed in the OFF state in any patient. One minor, asymptomatic hemorrhage occurred during surgery in one patient along one of the needle tracts. This resolved without sequelae.

Two AEs (both low dose) were deemed possibly related to the cell product. One AE involved the re-emergence of ON dyskinesias in one participant that were present from 5 to 10 months after transplantation, despite a reduction in dopaminergic medication, and causality to the ATIMP could not be ruled out. The participant has since stabilized, indicating that this AE was not related to the mature, functional graft. In another participant, a transient increase in parkinsonian symptoms was noted in the first 3 weeks after the operation. This patient did not respond well to medication during a period of approximately 1 week, and a possible contribution of surgery, concomitant medications and/or the ATIMP (graded ‘possibly related’) could not be ruled out.

A higher proportion of AEs was attributed to immunosuppression (33% in the low-dose group, 56% in the high-dose group; Table 3 ), including abnormal blood tests as expected. These events were manageable and consistent with the known profiles of immunosuppressive therapies. At the time of this interim analysis, all surviving participants have either completed or are tapering off their immunosuppressive therapy, as per the protocol.

All five tracts per hemisphere were confirmed to be accurately placed within the putamen in each participant, as assessed by postoperative cranial MRI (Fig. 2a–c ). Notably, two participants exhibited T2-weighted MRI hyperintensities outside the graft site at 1 and 6 months after transplantation, respectively, consistent with gliosis along the needle tract, similar to findings reported in a comparable trial 19 . One minor, asymptomatic hemorrhage occurred in a single trajectory (1 out of 80 trajectories), which resolved without sequelae.