Phase I trial of hES cell-derived dopaminergic neurons for Parkinson's disease

Abstract

Parkinson's disease is a progressive neurodegenerative condition with a considerable health and economic burden¹. It is characterized by the loss of midbrain dopaminergic neurons and a diminished response to symptomatic medical or surgical therapy as the disease progresses². Cell therapy aims to replenish lost dopaminergic neurons and their striatal projections by intrastriatal grafting. Here, we report the results of an open-label phase I clinical trial (NCT04802733) of an investigational cryopreserved, off-the-shelf dopaminergic neuron progenitor cell product (bemdaneprocel) derived from human embryonic stem (hES) cells and grafted bilaterally into the putamen of patients with Parkinson's disease. Twelve patients were enrolled sequentially in two cohorts-a low-dose (0.9 million cells, n = 5) and a high-dose (2.7 million cells, n = 7) cohort-and all of the participants received one year of immunosuppression. The trial achieved its primary objectives of safety and tolerability one year after transplantation, with no adverse events related to the cell product. At 18 months after grafting, putaminal ¹⁸Fluoro-DOPA positron emission tomography uptake increased, indicating graft survival. Secondary and exploratory clinical outcomes showed improvement or stability, including improvement in the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part III OFF scores by an average of 23 points in the high-dose cohort. There were no graft-induced dyskinesias. These data demonstrate safety and support future definitive clinical studies.

Fig. 1. The study design.

Summary of the study design. Patients were enrolled sequentially into a low-dose then a high-dose cohort. The diagram indicates the timeline of immunosuppression, monthly laboratory and clinical assessments, and imaging studies throughout the study. Ongoing follow-up is anticipated for a minimum of 5 years.

Fig. 2. Clinical outcomes 18 months after transplantation.

a,b, Secondary end points: individual MDS-UPDRS Part III OFF scores in the low-dose (a) and high-dose (b) cohorts at the baseline and at different timepoints after transplantation. c,d, Individual PD diary good ON time at the baseline and at different timepoints after transplantation in the low-dose (c) and high-dose (d) cohorts. Bold lines are mean ± s.d.; exact values are given as mean (s.d.) beneath each data point. e–h, Exploratory end points: individual scores on MDS-UPDRS Part III ON (e), Adjusted PD diary OFF time (f), MDS-UPDRS Part II (g) and UDysRS objective subscore (h) at the baseline and at different timepoints after transplantation in the low- and high-dose cohorts. Bold lines are mean ± s.d. The baseline value (0 months) is defined as the last recorded value before surgery. The double dagger symbol (‡) indicates the exception that, for MDS-UPDRS Part III OFF at 18 months after transplantation, n = 6. The total possible score for the MDS-UPDRS Part III scale is 132, for the MDS-UPDRS Part II scale is 52 and for the UDysRS objective scale is 44. Good ON time is the sum of ON time without dyskinesia and ON time with non-troublesome dyskinesia. Source data

Fig. 3. PET images of ¹⁸F-DOPA uptake signal in the striatum.

Images of the ¹⁸F-DOPA PET uptake signal at multiple sections through the striatum, presented as the mean uptake of all patients (n = 12 at all timepoints except at 18 months, for which n = 11). Images of ¹⁸F-DOPA uptake were produced by dividing each original PET image by the occipital count and then subtracting 1. Formula: image of ¹⁸F-DOPA uptake = (PET image/occipital count − 1).

Extended Data Fig. 1. Patient Disposition.

Diagram detailing the disposition of all participants. The 12 participants who passed screening were enrolled sequentially into the low-dose cohort (N = 5) or high-dose cohort (N = 7).

Extended Data Fig. 2. Representative Magnetic Resonance images.

Representative axial T1-weighted and sagittal Flair MRI images obtained at baseline, 6 months, 12 months and 18 months. No evidence of intracerebral haemorrhage, mass, lesion, and/or cellular overgrowth. Transplanted cells were indiscernible; needle tracks exhibit gliosis as expected and are best seen in the lower panels. MRI: Magnetic resonance imaging.

Extended Data Fig. 3. Quantification of ¹⁸F-DOPA PET uptake in the striatum.

Volume of interest (VOI)-based analysis of ¹⁸F-DOPA PET uptake signal in the anterior putamen (a), posterior putamen (b) and the caudate (c) at baseline, 12 months and 18 months, for individual patients in the low and high dose cohorts. Data is obtained via the VOI method as described in the Methods section. N = 12 for all timepoints with 2 exceptions: one patient missed the 18-month timepoint scan, and another patient had their 18-month timepoint scan performed at week 91 (at ~21 months) post grafting (data included). Bold lines in each panel represent the mean ± SD. Source data

Extended Data Fig. 4. PET images of ¹⁸F-DOPA PET uptake signal in the two dose cohorts.

Images of ¹⁸F-DOPA PET uptake signal at multiple sections through the striatum, presented as mean uptake at baseline, 12 months, and 18 months in the low dose cohort (top) and high dose cohort (bottom). Images were produced by dividing each original PET image by occipital count and then subtracting 1. PET, positron emission tomography. N = 12 for all timepoints with 2 exceptions: one patient missed the 18-month timepoint scan, and another patient had their 18-month timepoint scan performed at week 91 (at ~21 months) post grafting (data included).