The implantation of dopaminergic neurons derived from human induced pluripotent stem cells (iPSCs) has for the first time been shown to restore nerve function and improve movement in monkey models of Parkinson’s disease (PD), in a new Japanese study.
The findings of the preclinical study, published in the Aug. 31, 2017, edition of Nature, indicate the approach could potentially be applied to the clinical treatment of human patients with PD. Clinical trials of the procedure are expected to begin as early as next year.
The second most common neurodegenerative disorder after Alzheimer’s, PD is a chronic, progressive disease of unknown etiology affecting approximately 10 million people globally. While drugs and other treatments can manage its symptoms, there is currently no cure for PD.
Induced pluripotent stem cells (iPSCs) are adult cells that have been reprogrammed to become capable of differentiating into a range of different cells. They are a promising source for cell-based therapy to replace damaged nerve cells in the brains of patients with neurological disease, which are dopaminergic neurons in PD patients.
To date, however, long-term studies of human iPSC-derived dopaminergic neurons in primate models of PD have not been performed.
Therefore, researchers led by Jun Takahashi, a professor in the Center for iPS Cell Research and Application at the University of Kyoto, assessed the safety and function of such neurons by implanting them into the brains of monkeys exhibiting a model of PD.
“We used MPTP-treated monkeys, which replicate well the behavior and histology, including the loss of dopaminergic neurons, that are seen in PD patients,” Takahashi told BioWorld.
The researchers demonstrated that the human-derived cells displayed long-term survival for up to two years, functioned as midbrain dopaminergic neurons, and restored a range of movements in the monkey models of PD.
“Using fluorodopa positron emission tomographic (F-DOPA PET) scanning, we showed dopamine synthesis by the grafted cells, which resulted in behavioral recovery, with a recovery rate in behavior scores of approximately 50 percent being seen at 12 months,” said Takahashi.
Those findings “indicate that our human iPSC-derived dopaminergic progenitor cells are clinically applicable to the treatment of PD patients,” he noted.
The number of surviving dopaminergic neurons varied between animals, and the authors identified genetic signatures that may affect survival, which could be used for selecting the best cell lines in a clinical setting.
“We suggest that that protein delta homolog 1, a protein that in humans is encoded by the Dlk1 gene, might be a predictor of a good clinical outcome, but that is mere speculation based on the gene expression profile,” said Takahashi.
In the future, further investigations will be needed to clarify the best markers for good donor cells, but the present results could contribute to development of cell-based treatments for neurological diseases.
The use of iPSC transplantation has been complicated by problems including the risk of complications, in particular cancer formation and immune rejection. However, in the present study, the cells did not form any tumors in the brains for at least two years.
Importantly, the newly transplanted cells elicited either no or only a mild immune response. That is consistent with the findings of a related study published in the Aug. 14, 2017, edition of Nature Communications, in which Takahashi and colleagues described an approach that improved survival of the iPSC-derived neurons after transplantation.
They demonstrated that matching the major histocompatibility complex (MHC) group of proteins, which are important in eliciting immune responses, in the iPSCs to the MHC of the recipient improved graft survival by reducing the immune response against the derived neurons.
“This revealed that MHC matching reduced the immune response in the case of allogeneic transplantation,” said Takahashi. “However, it did not completely prevent the immune response, so this approach should be used together with immunosuppression, although MHC matching could reduce both the required dose and duration of immunosuppressant treatments.”
Taken together, “our findings provide strong evidence to support the clinical application of iPSC-derived dopaminergic progenitors,” he said.
“Our next step will be a clinical trial of this allogenic transplantation procedure in PD patients,” he added. “We plan to begin a clinical trial by the end of 2018, although prior to that, we need to confirm efficacy and safety of the iPSC-derived dopaminergic progenitors that will be used in the trial.”