0514 GMT March 20, 2018
Professor Jun Takahashi of the Center for iPS Cell Research and Application (CiRA), Kyoto University, Japan, and his colleagues are engaged in a project to develop a method to treat Parkinson’s disease through induced pluripotent stem cells (iPS cells), which will revolutionize the treatment of this disease if it properly achieves its goals. The main objective is to increase the amount of dopamine for treatment.
I met Professor Jun Takahashi (MD, PhD), a professor at the Department of Clinical Application of CiRA and his colleague, a Senior Lecturer and Science Writer at the CiRA Mr. Peter Karagiannis (PhD), to discuss the said project.
Parkinson’s disease develops when the number of DA neurons, or dopamine-producing neurons, decreases, which leads to less dopamine.
Professor Takahashi said, “We aim at the development of cell replacement therapy using iPS cells for intractable neurological diseases, mainly Parkinson’s disease, for which clinical experience has been accumulated by the transplantation of fetal midbrain cells, and its effect and problems have been clarified.”
Touching on the advantages of iPS cell over other methods, Karagiannis said, “iPS cells have many advantages. In the first place, an iPS cell can be differentiated to any cell. Moreover, iPS cells can be made from blood cells, so anyone donating blood, following proper consent, could also be donating iPS cells.”
In fact, the reason for focusing on iPS cells is that they proliferate infinitely and can differentiate into many types of cells (Pluripotency).
Professor Takahashi said, “Making iPS cells takes three months and testing them six months. Neurons take one to two months. CiRA intends to have iPS cells and check their safety for human use. In fact, CiRA has made a cell line and can use them.”
He added, “We here in our center are focusing on iPS cells because of many reasons. For instance, when fetal cell is used, definitely the ethical issue pops up. In addition, you know, we face the limitation of number and availability when we want to use fetal cells.”
However, Professor Takahashi said, “We have not yet used iPS cells for human patients, because the Japanese government demands very strict vigorous tests for safety.
“The Center for Biological Development (under the supervision of Dr. Masayo Takahashi) in September 2014 made retinal pigment epithelial cells from human iPS cells and transplanted them to the eye retina. The idea was to prevent further degeneration.”
However, Karagiannis said, “It was a specific case and we cannot generalize it.
“The mission of CiRA is to contribute to new therapies using iPS cell technology. Blood and skin cells are used to make iPS cells and use them for cell therapy.”
Takahashi however said, “The main method then will be iPSC-based transplantation.
“In this method, the iPS cells are (almost always blood cells or fibroblasts) that are reprogrammed. The iPS cells are then differentiated to neurons for PD, retinal/corneal cells for eye diseases, etc.”
Elaborating on the method the CiRA uses in the said project, Professor Takahashi said, “Let me explain to you the way we want to use iPS cells for treatment of Parkinson’s disease. Before explaining our mechanism, it is better to give you a brief explanation about the disease itself.”
“You know,” he said, “in this disease the number of DA neurons decreases which would lead to less dopamine and finally culminates in the development of Parkinson’s disease.”
Currently, there are four methods used for the treatment of this disease: Medicine; electric stimulation (DBS); gene therapy; and cell transplantation (fetal cells and stem cells).
But, in fact, iPS cell transplantation is a regenerative medicine for Parkinson’s disease, Professor Takahashi said.
In this method, iPS cells are turned into DA neurons and then injected into brain. Indeed, ES, iPS cells can be expanded unlimitedly. It may be also possible to generate and/or isolate DA neurons.
“In our research, we have made considerable progress,” he said.
Autologous transplants use cells from the patient. Allogeneic transplants use cells not from the patient. It is assumed autologous transplants will not elicit an immune response. Allogeneic transplants, on the other hand, require immuno suppressants. However, the survival of the transplant is based not only on the immune response but also the quality of the cells. Therefore, one cannot assume that autologous or allogeneic have better survival.
Professor Takahashi and his colleagues at the center have performed studies on the improvement of neuropathic symptoms by the induction of dopamine-producing neurons using ES cells and cell transplantation in model animals, and found that the motor function could be improved by the transplantation of cynomolgus monkey ES cells and induction of dopamine-producing nerves in a monkey Parkinson’s disease model, and the transplantation of nervous system cells selected following differentiation induction inhibited tumor formation.
The CiRA’s project is not unchallenged. There are many problems and challenges faced by Professor Takahashi and his colleagues in their endeavor to materialize the project.
According to Professor Takahashi, there are many problems to be overcome to clinically apply cell transplantation using ES and iPS cells, and these are being resolved one by one: 1) The neural induction involving no animal-derived factors, 2) selection of cells to inhibit tumor formation, 3) inhibition of cell death and immunosuppression following transplantation, and 4) establishment of assessment systems to confirm the long-term effects and safety.
“Since we have already performed dopamine-producing nerve induction from human ES cells and its transplantation into a cynomolgus monkey model, behavioral analysis, and imaging analysis, firstly, we will optimize conditions for neural induction from human iPS cells, and confirm the safety in the primate model,” Takahashi added.
The Center for iPS Cell Research and Application (CiRA) was established in January 2008 as part of the Institute for integrated Cell-Material Science (iCeMS), Kyoto University. It was founded to serve as a global leader in iPS cell research; conduct basic and applied research of iPS cells with the goal of new regenerative medicine; train future leading scientists and promote research collaboration with Kyoto University’s Institute for Integrated Cell-Material Sciences, Graduate School of Medicine, and University Hospital.
In April 2009, the iPS Cell Research Fund was set up. In April 2010, CiRA was reorganized as an institute independent of iCeMS. In 2013, Uehiro Research Division for iPS Cell Ethics was established to look after ethical issues. From February 2010 to March 2016 CiRA expanded its activities and overall completed three buildings for its activities.