“This is an important step in the translation of iPSC-derived technology to clinical cell transplants in Parkinson’s,” Patrik Brundin, a neuroscientist at the Van Andel Institute in Michigan who did not participate in the work, tells The Scientist. “There were no major surprises, but these were essential experiments that were required before moving forward to clinical trials.”
Kyoto University neurosurgeon Jun Takahashi and colleagues generated eight iPSC lines from skin or blood cells collected from seven human subjects—three with PD and four without—and derived dopaminergic progenitors from these cell lines. Then, the researchers grafted the reprogrammed cells into the brains of 2- to 3-year-old, male cynomolgus monkeys (Macaca fascicularis) that had been treated with the neurotoxin MPTP, which kills dopamine-releasing neurons and results in PD-like movement defects.
The seven monkeys that received either cells derived from individuals with PD or healthy individuals showed a 40 to 50 percent improvement in symptoms—such as increases in spontaneous movements and decreases in tremors—for at least a year, compared to vehicle-injected controls. The authors confirmed that cells derived from both PD patients and healthy donors made dopamine in vivo, at levels about half that of cells in normal monkeys. The grafted cells also sent out fibers, survived for the 24-month duration of the experiment, and did not form teratomas.
“The combination of imaging methods for evaluation of the cells and the [behavioral] evaluation of the animals is very powerful,” says Marina Emborg, a neuroscientist at the University of Wisconsin-Madison who did not participate in the work. Emborg explains that although the results are encouraging overall, the authors report differences in dopamine production and innervation of the host tissue by the grafts, so it will be necessary to identify the best cell lines in order to improve replicability.
“The next steps are the basics of cell production,” says Ole Isacson of Harvard Medical School. Isacson did not participate in this study, but he leads a team in developing strategies for generating new dopamine neurons from iPSCs for the treatment of PD. “In order to have [these cells] in the clinic, we need to freeze them down, we need to test them for safety, and we have to know exact specifications under very controlled conditions. Those steps are taking us more time than scientific discovery.”
The authors acknowledge these issues in their paper. And, according to Takahashi, they are addressing them as they prepare for the next steps. “We need to confirm efficacy and safety of the cells which will be used in the clinical trial. We are now doing these experiments using rats and mice,” he writes in an email to The Scientist.
In the planned clinical trial, the research team will use iPSCs derived from healthy donors, not from the subjects’ own cells, which could raise issues with graft rejection. But Takahashi’s group also published an accompanying paper today in Nature Communications that offers a partial solution. In the study, the researchers show that matching donors and recipients for the major histocompatibility complex, which is involved in self versus non-self recognition, lowers the risk of graft rejection in monkeys. Based on these results, the researchers will attempt to match donor and recipient types of the human version of major histocompatibility complex—human leukocyte antigen—and use immunosuppressant drugs in the upcoming clinical trial. (Already, doctors in Japan have begun administering a cell therapy based on iPSCs from donors to treat macular degeneration.)
“We’re looking at ways of replacing cells to make degenerating brains work better,” says Isacson. “This is really the leading edge of that.”
T. Kikuchi et al., “Human iPS cell-derived dopaminergic neurons function in a primate Parkinson’s disease model,” Nature, doi:10.1038/nature23664, 2017.
A. Morizane et al., “MHC matching improves engraftment of iPSC-derived neurons in non-human primates,” Nature Communications, doi:10.1038/s41467-017-00926-5, 2017.