In 2018, CiRA Prof. Jun Takahashi joined a team of surgeons to announce the world's first clinical trial using iPS cell products for Parkinson's disease (UMIN000033564, JMA-IIA00384) (iPS cell-based Parkinson's disease therapy administered to first patient). The therapy involved preparing dopaminergic progenitor cells from iPS cells and transplanting them into patients' brains. For a cell therapy to reach the clinical stage, it must satisfy a set of standards, but because this was the first brain surgery using iPS cells, no universal standards exist for these cells.

In a new study seen in Nature Communications, the Takahashi lab shares its preclinical results that led to permission from the Japanese government for the clinical trial. The authors expect their data to provide a basis for other scientists seeking to use iPS cells and other stem cells in brain therapies.

The most known symptom of Parkinson's disease is slowness of movement, tremor, or rigidity. At the cellular level, this symptom is attributed to a loss of dopaminergic neurons in the brain. While no cure exists, one strategy taken by neurosurgeons is to transplant dopaminergic progenitor cells into the brain, where they develop into dopaminergic neurons. This is the approach Takahashi has pursued for several decades.

"I have been using stem cells to develop a curative cell therapy since the 1990s," he says.

The study outlines an assortment of experiments requested by the Japan Pharmaceutical and Medical Devices Agency (PMDA), which provides guidance to clinicians and researchers seeking to conduct clinical trials in the country.

Tests include checking the safety of the iPS cells, the quality and purity of the dopaminergic progenitor cells, and their state and function when transplanted into animals such as mice and rats.

"We have worked many years with the PMDA to prepare cells that fulfill Japanese regulations. We want this paper to guide groups in other countries to conduct the same clinical trials," Dr. Daisuke Doi, one of the neurosurgeons managing the project.

One of the issues involving iPS cells is stability. The reprogramming process risks activating cancer genes.

"We extensively investigated for mutations associated with hundreds of cancer-related genes. We also investigated epigenetic modifications, because methylation at the transcriptional start site can activate cancer genes," explains Doi.

Tests verified that the any risk of cancer was negligible and also showed that when transplanted into the animals, the dopaminergic progenitor cells became mature dopaminergic neurons, a conversion that corresponded to recovered impaired movement.

As would be expected for a study that received approval, the results passed all the conditions set by the PMDA.

"My wish is that other neuroscientists and neurosurgeons will see iPS cells as a viable option for clinical treatment," says Takahashi.

• doi: 10.1038/s41467-020-17165-w