How should next-generation regenerative medicine be promoted?

From organ regeneration to functional regeneration

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In recent years, remarkable progress has been made in the field of regenerative medicine utilizing induced pluripotent stem (iPS) cells, suggesting the availability of treatment options for intractable diseases that otherwise cannot be managed by existing medicines. A growing number of novel treatment methods, including transplantation of organs grown from iPS cells, have been increasingly developed, marking a revolution in the field of medicine. The benefits that advancements in regenerative medicine would provide remain unclear. Professor Matsuyama positively views next-generation regenerative medicine and believes that it could completely overturn the current concept of regenerative medicine. If realized, it would radically decrease medical costs and enable more people to receive less-invasive treatments.

Akifumi Matsuyama

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Akifumi Matsuyama

Professor, Department of Regenerative Medicine

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Increasing application of regenerative medicine in real-world settings

Since the beginning of 2018, there has been an upsurge in the news about regenerative medicine that uses iPS cells. First, in May, a clinical study that involved transplantation of a myocardial sheet created from iPS cells into a patient was approved by the Ministry of Health, Labour and Welfare of Japan, making it the second clinical study in which a cell pharmaceutical product created from iPS cells was transplanted into a patient. The first such study targeted macular degeneration, an intractable eye disease.

In late July, it was announced that a clinical study involving the transplantation of nerve cells created from iPS cells into the brain of a patient with Parkinson’s disease would be initiated by the end of the year. In August, a clinical study protocol for increasing the number of platelets from iPS cells of a patient and administering them back to the patient was submitted to the government. A decade has passed since Professor Shinya Yamanaka (Kyoto University) developed human iPS cells, and their application in clinical settings is currently expanding at a remarkable pace.

Professor Matsuyama stated, “What is the essence of regenerative medicine, which is represented by iPS cells? I figure that if I could describe it in one word, it would be ‘hope’.” The expansion of regenerative medicine has offered hope that diseases that cannot be cured through existing treatment options can be treated going forward; this is truly encouraging for patients with intractable diseases.

Nevertheless, regenerative medicine has encountered several obstacles throughout its development to date. It took a considerable amount of time for clinical studies on iPS cells to be initiated since the technology was pioneered. It goes without saying that during this period, substantial research was made into the development of iPS cells themselves.

That said, irrespective of how we arrived at this point, various regulations need to be set in place to apply the findings of such research to clinical settings. Although it is the government that implements such regulations, no one in the government has had expertize in iPS cell technology as these were a completely novel invention. In this scenario, Professor Matsuyama, who is a key player in developing a regulatory framework for the application of iPS cells to the clinical setting, has been playing a pivotal role in bridging the gap between academia and the government.

Moving forward through negotiations between the government and academia

Upon learning of successful iPS cell development, doctors across Japan began considering the clinical application of iPS cells. As iPS cells could differentiate into any type of cells, they could pave the way to saving many lives, which existing treatments are unable to do.

As iPS cells have never previously existed, there were no regulations or rules regarding regenerative medicine using iPS cells. Conducting research to saving people’s lives does not mean offering freedom to do anything. Even if specific in-vivo studies were allowed on animals, it would eventually be necessary to conduct clinical trials in humans to apply the results to the clinical setting.

The question is how to ensure safety in clinical trials. From a government standpoint, no clinical trial should cause the loss of human life. Hence, the implementation of relevant regulations would require great care, and the details would need to be stringent.

However, stringent rules often hinder the progress of research in the clinical setting. While both the government and academia aim to develop regenerative medicine, they are witnessing issues raised from different angles.

To close this gap, the then Adjunct Professor Matsuyama, who was assisting Professor Sawa in Osaka University, was invited.

“I was a subordinate to Professor Sawa, who is a leading authority in regenerative medicine. I have a slightly unique background as I gave an exam for medical school after I started studying in the law department of a university. I still love law, and when I get tired of medical research, I enjoy reading the Six Codes (Roppô Zensho). Thanks to this, Professor Sawa started taking me with him to meetings with the Ministry of Health, Labour and Welfare. As I wrote meeting drafts and other documents, the government started asking Professor Sawa to send me to them.”

Professor Matsuyama was subsequently appointed as a Senior Specialist for Human Stem Cell Clinical Research in the Health Service Bureau, the Ministry of Health, Labour and Welfare. Since then, he was involved in several tasks, from the implementation of regulations for regenerative medicine to the allocation of research budgets. Through a series of tasks, he learned the mechanism of allocating research budgets and extended his network on the government side.

“After I served as an Assistant Director of the Clinical Trial Promotion Office at the Health Policy Bureau, I returned to Osaka University with specialized knowledge on research, regulation, and current trends in research budget allocation. The experience of setting up regulations has been helpful for me in carrying out my current role.”

Building networks and increasing experience for utilization in research

Based on the New Growth Strategy, which was finalized in the Diet in 2010, the Highway Program for Realization of Regenerative Medicine, a project for realizing the application of regenerative medicine to the clinical setting, was launched. In the project implementation, Professor Matsuyama was appointed as a leader in providing long-term support to, and facilitating communication between, the Ministry of Education, Culture, Sports, Science and Technology and the Ministry of Health, Labour and Welfare for research and development.

“The project had been allocated 110 billion for a period of 10 years. To support Professor Yamanaka as well as Professor Okano from Keio University and other researchers working in the field of iPS cells, including Professor Eto, I took on a role of negotiating with the Ministry of Health, Labour and Welfare and PMDA. I was involved in the tasks of setting up guidelines for clinical studies that use human stem cells and the new law for regenerative medicine (the Act on the Safety of Regenerative Medicine) and was able to deepen my experience. Thereafter, I returned to conducting research and began serving as the Director of the Center for Rare Disease Research and Support, the National Institutes of Biomedical Innovation, Health and Nutrition.”

Despite his unconventional career background as a regenerative medicine researcher, Professor Matsuyama never stopped engaging in research. His entire professional career culminated in the position of Professor at the Department of Regenerative Medicine, Fujita Health University.

Led by the President’s hope, “I want to make a change to healthcare across the globe”

On April 1, 2018, Professor Matsuyama started his term as a Professor at the Department of Regenerative Medicine, the School of Medicine, Fujita Health University, and as Director of the Regenerative Medicine Support Promotion Facility, the Center for Research Promotion and Support. Professor Matsuyama said that the strong hope of President Kiyotaka Hoshinaga made him decide to assume the roles.

“The President enthusiastically said that he wanted to make Fujita Health University a globally respected university and wanted to make a change to healthcare across the globe from the university. He explained to me that three core research areas had been determined, namely, cancer, clinical genome, and regenerative medicine. He graciously told me that he wanted me to take on responsibilities for regenerative medicine research.”

Just before this, President Hoshinaga had contacted a startup company that was planning to create somatic stem cells by stocking placentae and using them for regenerative medicine. He intuitively felt that this could form the core of the research and invited Professor Matsuyama to be the project leader. Undeniably, the President made this decision because he highly acknowledged the research performance, career, and network of Professor Matsuyama.

“The idea of using placentae was eye-opening. I was impressed by the President’s perspective and inspiration. The placenta is an organ that connects the mother and the baby. If the blood of the mother were to directly flow into the baby, it would cause an immunoreaction. The placenta has an anti-inflammatory action that suppresses such immunoreactions. Therefore, regenerative medicine that utilizes the stem cells of the placenta has the potential to suppress connective tissue diseases. I saw a tremendous potential in the regenerative medicine that Fujita Health University was aiming for: driving the growth of a startup company in its seed stage through the President’s strong management within the regulatory framework of Japan, which is something that I have expertize in.”

Moving from organ regeneration to functional regeneration

The application of regenerative medicine is not limited to one specific purpose—it spans multiple areas. Current research primarily focuses on developing a treatment method to regenerate organs and nerve cells from iPS cells and transplant them to replace organs whose functions have been reduced because of reasons such as disease.

Conversely, Professor Matsuyama is aiming to develop regenerative medicine that can regenerate the functions of organs rather than requiring organ transplantation. Although both of these approaches fall under the field of regenerative medicine, they are markedly different and are associated with very different costs. If a regenerative medicine that regenerates only organ functions could be realized, it could lead to a considerable reduction in medical costs compared with the costs associated with regeneration of organs, which require longer periods and substantially more work.

“In addition, because placentae are regulated medical waste, it is easy to handle them, and it is generally possible to collect young, healthy cells. They are useful for medical practice as it is possible to secure the stable supply of placentae to use as base materials.”

Presently, chronic myocardial infarction and cirrhosis have been set as treatment targets in which somatic stem cells created from placentae are used.

Next-generation regenerative medicine that exceeds current limits

It is conceivable to create the number of somatic stem cells required to treat 100–200 patients from a single placenta. The three essential factors for cell production are a dedicated center, culture solution, and the expertise of staff who are involved in operations.

First, at Fujita Health University, the Cell Processing Center (CPC) for manufacturing cells, which is currently under construction, will ensure efficacy, safety, and quality. The Center is scheduled to be competed next year. With regard to culture solution, owing to the tremendous effort by reagent manufacturers, a growing number of quality products are available in the market. Now that the above two factors are secured, the last factor that markedly affects the quality of cells is the expertise of operation staff.

“Staff who have been working with me on research are extremely talented. This time, all of them will be transferred together. Moreover, in terms of the facility, a negative pressure-type CPC, which is very rare in Japan, will also be built by the Center. Therefore, going forward, I am envisaging the CAR-T therapy, which involves the genetic engineering of cells outside the body and putting them back into the body.”

Developing a simpler, more cost-effective method to save more lives

Another potential of regenerative medicine is drug discovery. It is true that iPS cells have extensively facilitated work for reconstructing the affected areas of the body and discovering chemical compounds that possess treatment efficacy; however, Professor Matsuyama holds an opinion toward the discovery of a drug that could lead to a paradigm shift in regenerative medicine.

“An example is regenerative medicine that uses a myocardial sheet for a patient suffering from heart failure. Because it costs large sums of money to construct a myocardial sheet requiring approximately 100 million cells, the total medical cost for such treatment will reach approximately 15 million yen. Meanwhile, the mechanism of how a myocardial sheet improves heart failure has already been clarified. This is called as a “cytokine effect.” Therefore, if we can create cytokines directly from somatic stem cells and apply them to the myocardium with materials such as gauze, this would cost less than the cost of surgery using a myocardial sheet. Moreover, if we can extract only cytokines and orally administer them, the treatment itself would be drastically simplified and the cost would reduce by a significant amount. This kind of treatment is called functional regenerative medicine. Next-generation regenerative medicine will be based on a completely different concept from that around which the current, organ regeneration-focused approach is centered. Thus, next-generation regenerative medicine could save more lives. I am prepared to devote the rest of my life to developing next-generation regenerative medicine to achieve this aim.”

Professor Matsuyama aims to establish next-generation regenerative medicine 10 years from now. His endeavor has just begun.