A phase I/II trial conducted at Kyoto University Hospital evaluated the safety and preliminary efficacy of bilateral transplantation of dopaminergic progenitor cells derived from allogeneic induced pluripotent stem cells in patients with Parkinson’s disease. Seven patients aged 50 to 69 years received dopaminergic progenitor transplants. The study's primary endpoints focused on safety, while secondary endpoints assessed motor symptom improvement and dopamine production over 24 months.
Key Findings
A total of 73 mild or moderate adverse events occurred, but no serious adverse events were reported. The most common adverse event was application site pruritus in four patients (57.1%). No tumorigenic growth was observed.
“This trial (jRCT2090220384) demonstrated that allogeneic iPS-cell-derived dopaminergic progenitors survived, produced dopamine and did not form tumors, therefore suggesting safety and potential clinical benefits for Parkinson’s disease,” Nobukatsu Sawamoto and colleagues reported in Nature.
Efficacy was evaluated in 6 patients. Improvements in MDS-UPDRS part III scores were observed in 4 patients (OFF) and 5 patients (ON), with mean changes of –9.5 points (–20.4%) and –4.3 points (–35.7%), respectively. Hoehn–Yahr stage improved in 4 patients.
Imaging Confirms Dopamine Production
Fluorine-18-l-dihydroxyphenylalanine (18F-DOPA) PET imaging revealed a 44.7% mean increase in the influx rate constant (Ki) in the putamen. The high-dose group showed a 63.5% increase, compared with 7% in the low-dose group. The ratio of Ki values in the putamen to the caudate increased in all patients, which indicated increased dopamine synthesis despite ongoing disease progression.
Methods and Treatment
The clinical-grade iPSC line (QHJI01s04) was derived from a healthy donor homozygous for a common Japanese haplotype which matched approximately 17% of the Japanese population.
Three patients received a low dose (2.1 to 2.6 × 10⁶ cells per hemisphere) and four received a high dose (5.3 to 5.5 × 10⁶ cells per hemisphere). Tacrolimus was used for immunosuppression but was reduced at 12 months and discontinued at 15 months.
To enrich dopaminergic progenitors and exclude nontarget cells, CORIN+ cells were isolated and cultured into aggregate spheres before transplantation into the putamen using neurosurgical navigation.
Clinical Implications
This trial marks the first clinical study of iPSCs for Parkinson’s disease and addresses ethical and logistical challenges that are associated with fetal ventral mesencephalon (hfVM) transplants. Unlike previous hfVM trials where graft-induced dyskinesias (GIDs) occurred, no GIDs were observed. A mild increase in dyskinesia was noted in six of seven patients and was consistent with drug-induced dyskinesia.
MRI showed gradual graft volume increases over 24 months, with no tumor-like enlargement.
The researchers concluded that allogeneic transplantation of iPSC-derived dopaminergic progenitors appears safe and shows early indications of efficacy. They proposed combining this approach with gene therapy, pharmacologic treatment, or rehabilitation in future strategies.
Conflict of interest disclosures were reported in the original publication.