Kobe Eye Center 5F, 2-1-8 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 Japan
March 8, 2021
Fiscal year end：
End of February
President Masayo Takahashi
Moving toward the practical application of regenerative medicine using iPS cell-derived pigment epithelial (iPS-RPE) cells
About Retinal pigment epithelium (RPE)
Retinal pigment epithelium (RPE) is a layer of cells formed by paving hexagonal, brown pigmented cells located on the outermost side of the retina. RPE cells play an important role in maintaining our visual function by directly contacting and protecting photoreceptor cells, an important part of the retina . Therefore, it is known that abnormalities in RPE cells (RPE deficiency state) cause a wide variety of retinal degenerative diseases such as age-related macular degeneration. Unfortunately, even with advanced medical technology, there is no way to cure degenerated retinal cells.
Our clinical experience of RPE cell transplantation
We have focused on research intending to regenerate the retinal function of patients having retinal degeneration. One of our main projects is the iPS cell-derived RPE (iPS-RPE) cell transplantation. In the past, the research team of retinal regeneration Pj succeeded in the transplantation of iPS-RPE products derived from autologous and allogeneic origins for the patient with wet age-related macular degeneration prepared in suitable formulations for disease conditions first in the world [2,3,4]. So far, the safety of the iPS-RPE has been confirmed for both autologous and allogeneic origins. In allogeneic transplantation, it was found that by combining the transplanted cells matching the patient's HLA, rejection can be safely managed without administration of immunosuppressants. The visual acuity of the transplanted patient is still maintained. Given these results, we are convinced that regenerative medicine using iPS-RPE cells has taken a good step toward practical use.
Toward the practical application of iPS-RPE cell transplantation
Currently, we are conducting three projects toward the practical application of iPS-RPE cell transplantation.
Optimization of manufacturing methods: We perform research for optimization of raw materials, manufacturing method, and quality control test, aiming at a system that can stably supply iPS-RPE cells with improved safety and quality.
Optimization of transport and transplantation methods: In order to spread iPS-RPE cell transplantation, it is quite important that cell products are transported from the cell manufacturing facilities to medical institutions throughout Japan and around the world in the best condition. We will conduct research to provide the most suitable transplantation method for the patient's retinal condition.
Clinical protocol optimization: We are preparing to conduct clinical studies with our collaborative research institute, the Kobe Eye Center Hospital. We will optimize the clinical protocol for iPS-RPE cell transplantation together with the Kobe eye center hospital via conducting the clinical studies targeting RPE impaired diseases, including various retinal degenerative diseases, caused by abnormalities of RPE cells to expand the indications and to actively promote new ophthalmologic examination methods. We will optimize the clinical protocol for iPS-RPE cell transplantation.
 About RPE:
 Takagi S, Mandai M et al. Opthalmol Retina 2019
 Mandai M, Watanabe A et al. N Engl J Med 2017
 Sugita S, Mandai M et al. J Clin Med 2020
Retinal regeneration using stem cell therapy
The retina and retinal diseases
The eye functions similar to a camera. Light enters the eye through the cornea and lens, and is projected to the retina, located in the back of the eye. The retina is a specialized tissue for light perception, and is often compared to the film or the sensor in a camera. But the retina is much more than a light sensor, it processes visual information, and efficiently sends it to visual centers in the brain. The basic structure of the retina is reflective of its function, with different layers mediating the sensing, processing, and output of visual information.
Retinitis Pigmentosa is a genetic disorder that involves the degeneration and/or loss of the photoreceptor cells. As the progression of the disease is very slow, patients are often unaware of symptoms, and it is diagnosed when symptoms become more severe. There are no effective treatments for this disease, and patients have very limited options as they gradually lose their sight.
Cell therapy | Photoreceptor cell transplantation
Retinitis Pigmentosa is typical of the many disorders that affect the photoreceptor cell. Although patients' conditions may vary, and numerous mutations may cause the disorder, a common theme in Retinitis Pigmentosa is that although photoreceptor cells degenerate, the other layers of the retina remain relatively unaltered.
We think that it is possible to restore visual functions by restoring the lost photoreceptor cells or by restoring their function. This would be a fundamentally different approach from traditional treatment strategies, as it would allow to treat patients regardless of the underlying condition or cause gene. However, cell regeneration of photoreceptor cells, which are neurons, had been considered challenging. The Retinal Regeneration Project team have shown that retinal regeneration is indeed possible through research using model animals including mice, rats, and monkeys. We have shown that stem cell derived photoreceptor cells can be transplanted to degenerate retinas and restore light responsiveness, and transmit visual information to downstream cells. We continue our research to better understand the retina to develop more effective treatments.
Automation of cell culture processes fully utilizing robot and AI technologies
Basic research supporting regenerative medicine research
There are currently a large number of clinical research activities and trials on-going in efforts to find and develop new therapies, including regenerative medicine, for a variety of diseases. Every research activity and trial in humans is warranted by a vast number of basic research efforts conducted prior to the human stage. Many of the current basic laboratory studies are supported by “takumi-no-waza” (Japan’s traditional skills and craftsmanship) based on “tacit” (not explicitly written down or structured) knowledge and know-how of expert specialists with excellent skills in cell culture. However, the takumi-no-waza of master artisans is often extremely difficult to pass down and hence could face a big crisis of being lost at any time in the near future. The non-succession of takumi-no-waza is a serious problem that could mean non-feasibility of basic laboratory experiments and, of course, clinical research and trials based on these basic experiments. On the other hand, if we could establish certain systems able to facilitate the transfer of takumi-no-waza, basic research could potentially be further accelerated.
Cell production by robot and AI
The Laboratory for Retinal Regeneration in RIKEN worked with Robotic Biology Institute Inc., which develops a general-purpose humanoid robot "Maholo", and Epistra Inc., which develops AI and other information technologies, to establish next-generation biological experiments that make full use of robots and AI. Maholo is a robot that conducts experiments using the same tools as humans using two arms. The team had the challenge of transferring the skills and craftsmanship of the takumi as they are by separately copying hand and eye movements of the takumi and coordinating them in Maholo and AI. The team had already implemented some of the cell culturing procedures and techniques that have been employed at our laboratory into Maholo, and some of them are found to be more efficient than those of the takumi in achieving satisfactory laboratory works. Our company will further develop its technological development in the field of basic research to date and take on the challenge of developing a stable process to produce high-quality cells for clinical use.
 Ochiai and Motozawa et al., SLAS Tech (2020, in press)