Phase I/II trial of iPS-cell-derived dopaminergic cells for Parkinson's disease

Summary

The replacement of lost DA neurons with hfVM in patients with PD began in the 1980s22,23. Although PS cells are expected to be an alternative donor cell source to hfVM, the safety and efficacy of iPS-cell-derived DA progenitors remains unclear. This first clinical trial using iPS cells confirmed that iPS-cell-derived DA progenitors can survive without forming tumours and produce DA in the putamen of patients with PD. Moreover, there were no serious adverse events or GIDs. Four out of six patients showed improvement in MDS-UPDRS part III OFF at 24 months after transplantation, suggesting that grafted cells functioned as DA neurons.No serious adverse events were reported for all seven patients subjected to safety assessment. The graft size measured with MRI T2-weighted images gradually increased over the 24 months. However, no tumorigenic overgrowth was identified, as evidenced by the absence of 18F-FLT uptake, a marker of cellular proliferation, which was indirectly supported by results from the transplantation experiment using the same donor cells into PD model rats. Histological analyses at 24 or 32 weeks showed no tumour-like overgrowth, with less than 1.0% of cells being Ki-67 positive. Rather than proliferation, a previous animal study reported that the apparent increase in graft volume was due to the spread of the grafted cells9. While such effects may also apply to our trial, further confirmation through long-term follow-up and post-mortem histological examinations is necessary. The spectrum of adverse events was similar to those encountered with chronic DA replacement medication, tacrolimus administration and brain surgery. Neck stiffness and painful dystonia in the right upper limb were noted in PD01 during the drug-on state, a phenomenon possibly related to the grafts. Tacrolimus- and surgery-related adverse events were manageable and reversible.One critical concern about hfVM transplantation was GIDs4,5,24. In this trial, six out of seven patients showed a...