iPSC therapy success in Parkinson’s monkey models

Written by Lauren Pulling, Editor

Researchers from Kyoto University (Japan) have shown that human induced pluripotent stem (iPS) cell-derived dopaminergic (DA) progenitor cells can survive and function as midbrain dopaminergic neurons in a primate model of Parkinson’s disease (PD). The first study of its kind, this new research marks a major breakthrough in bringing iPS cell-based therapies for neurodegenerative disease closer to the clinic.
Previous clinical trials have explored the use of fetal-derived stem cells for PD, though the use of these cells remains controversial. This new preclinical study, however, published this week in Nature, has been hailed as being the final step before the first iPS cell-based therapy for neurodegenerative disease can be trialed in humans. Senior author Jun Takahashi (Kyoto University) commented: “Our research has shown that DA neurons made from iPS cells are just as good as DA neurons made from fetal midbrain. Because iPS cells are easy to obtain, we can standardize them to only use the best iPS cells for therapy.”

In the study, iPS cells were transplanted into macaque monkeys exhibiting a form of PD caused by the neurotoxin MPTP. Significantly, the neurons were functional 2 years post-transplantation, with histological studies and MRI and PET scans showing successful survival, expansion and function of the grafted cells. MRI and PET were also used to monitor immune response in the host brain, and cells sorted by the floor plate marker CORIN showed that no tumors had formed in the animals’ brains for at least 2 years. In addition, the animals exhibited an increase in spontaneous movement following transplantation.

The researchers developed DA neurons from different iPS cell lines, from both healthy donors and PD patients, and found that quality of the transplanted cells had a greater impact on success than quantity. Lead author Tetsuhiro Kikuchi (Kyoto University) added: “Each animal received cells prepared from a different iPS cell donor. We found the quality of donor cells had a large effect on the DA neuron survival.”

The team also investigated gene expression levels in the cell lines, finding that 11 genes were differentially expressed, including Dlk1. “Dlk1 is one of the predictive markers of cell quality for DA neurons made from embryonic stem cells and transplanted into rat. We found Dlk1 in DA neurons transplanted into monkey[s]. We are investigating Dlk1 to evaluate the quality of the cells for clinical applications,” said Kikuchi.

Overall, this preclinical study indicates that human iPS cell-derived DA progenitors are clinically applicable for the treatment of patients with PD. Next, the group hope to begin recruiting patients to receive the therapy before the end of the year, with Takahashi remarking, “This study is our answer to bring iPS cells to clinical settings.”

Sources: Kikuchi T, Morizane A, Doi D et al. Human iPSC-derived dopaminergic neuron function in primate Parkinson’s disease models. Nature 548, 592–596 (2017); www.cira.kyoto-u.ac.jp/e/pressrelease/news/170831-090000.html