November 8, 2017 2:49 pm JST
Cover story

Japan faces new competition in the race for 'regenerative medicine'

Promising iPS cell technology could lead to breakthroughs in Parkinson's disease, blindness and paralysis

KIYOSHI ANDO, Nikkei senior staff writer

Scientists at Tokyo's Keio University use a cell processing isolator to ensure a sterile environment. (Photo by Ken Kobayashi)

TOKYO -- Masaya Nakamura can pinpoint the moment when he decided to dedicate his life to researching and treating spinal cord injuries. It was during his second year at Keio University, and he and some other students had taken a skiing trip near Nagano. One of his friends crashed into a tree at high speed, leaving him paralyzed from the neck down. Nakamura had been studying to become a doctor but was undecided about what type of medicine he wanted to practice -- until then. "For more than 20 years, my motivation has been to cure my friend's spinal cord injury," he said.

Today, Nakamura is a professor in the department of orthopedic surgery at Keio University -- and a member of an elite group of scientists and doctors working in the field of "regenerative" medicine. These researchers believe the lives of patients suffering from Parkinson's disease, heart failure, blindness, paralysis and other debilitating health problems could be transformed using "induced pluripotent" stem cells, or iPS cells.

Nakamura says iPS cells could hold the key to curing people like his old friend. "No matter how good a surgeon I am, I cannot cure spinal cord injuries," he said. "That's why we do basic research" into iPS cells.

Discovered in 2006 by Japanese scientist Shinya Yamanaka of Kyoto University, iPS cell technology "reprograms" old cells, returning them to a state similar to those found in embryos -- essentially turning back the clock on mature cells. Japan has remained the world leader in iPS cell research since the discovery, thanks in part to an injection of about $1 billion over 10 years from the government after Yamanaka was awarded the Nobel Prize in 2012.

But global competition is rising, especially from the U.S., the U.K. and Canada, and many in the field are asking whether Japan can keep its lead in a field where it has been an undisputed pioneer. The key, researchers and industry leaders say, is for Japan to move quickly to the clinical application phase.

"Seeing how fast other countries are moving, I am deeply concerned that Japan may not be able to remain at the cutting edge of regenerative medicine," said Yuzo Toda, chairman of the Forum for Innovative Regenerative Medicine, an industry group.

At Keio University Hospital, Nakamura and his colleagues are racing toward clinical applications. Next year, they plan to transplant iPS cell-derived neural precursor cells -- these are cells that can grow into different types of neural cells -- into nine adult patients with spinal cord injuries. These transplants have shown promise in tests on mice. After injecting human iPS cells derived from neural precursor cells directly into the severed spinal cords in mice, some regenerative events took place within three months, significantly improving their ability to walk.

There are risks, however. If cells for transplant include "undifferentiated" cells -- most iPS cells "differentiate" into specialized ones, but some cannot -- then cancerous tumors may form.

 

But professor Hideyuki Okano, also of Keio University, has improved the painstaking process of differentiating iPS cells efficiently into neural precursor cells and screening out those iPS cells which are not fully differentiated. As a result, he has cut the possibility of including these undifferentiated cells to less than one-100,000th. With more than 2 million cells being transplanted, some 20 such cells, by simple arithmetic, will enter a recipient's body. In experiments on mice and in other tests, "such a number of them causes no tumor," Okano said.

The iPS cell-derived neural precursor cells Nakamura and Okano will use in their transplants are created, cultivated and stocked at Keio's state-of-the art cell processing center, whose exacting standards for cleanliness are like those of a semiconductor factory. In a shining silver tank, freshly produced cells are frozen by liquid nitrogen at a temperature of minus 196 C and stored until they are ready to be transplanted.

The iPS cells are delivered from Kyoto University's Center for iPS Cell Research and Application. CiRA's storehouse of frozen cells, created using blood cells, is known as "iPS Cell Stock."

Keio had hoped to have already started clinical applications this year, but those plans were dealt a blow when CiRA was forced to halt shipments of all its iPS cells made from umbilical cord blood cells after a tube was mislabeled. The delay was a serious setback, but researchers spent the time developing technologies to detect problems in transplanted cells.

"We would never waste the time (during the delay)," Nakamura said, pointing to a planned system to detect and prevent the malfunctioning of transplanted cells or the formation of cancerous cells. The researchers are using magnetic resonance imaging technology to create a color map that will highlight the condition of the sheaths that surround nerve cells, which are crucial to their function. Joining hands with General Electric of the U.S., Keio will seek to promote the mapping technology as a global standard.

Promise for Parkinson's

Yamanaka, along with then-assistant professor Kazutoshi Takahashi at Kyoto University, released their first research paper on iPS cells in August 2006. They had successfully produced iPS cells by using a simple method to implant four genes, subsequently called "Yamanaka factors," into the skin cells of mice. The team announced the successful creation of human iPS cells the following year.

Yamanaka coined the term iPS, saying he had adopted the small letter "i" from Apple's iPod that was popular then. His hope was that iPS would be as widely known as the iPod one day.

After Yamanaka was named the joint winner of the 2012 Nobel Prize in physiology or medicine, along with John Gurdon, a professor emeritus of the University of Cambridge, iPS fever broke out in Japan.

Kyoto University followed its completion of the first CiRA building in 2010 with the addition of a second in 2015; a third was added this year. The number of researchers at the facility increased from 120 at first to about 600 this year.

In further signs of the industry's growth, iPS Academia Japan, an organization dedicated to filing, maintaining and licensing iPS cell-related patents, manages 470 patent applications, with about 240 patents being issued in Japan, the U.S., Europe and other countries. The Forum for Innovative Regenerative Medicine, an industry group, started with 14 members in 2011 and has grown to about 200, including startups such as CellSeed, Healios, and ReproCELL.

Companies and researchers are pursuing two basic applications for iPS cells: regenerative medicine, which Nakamura is using in his spinal cord work, and drug development. Yamanaka has said that while using iPS for regenerative medicine will be important, the technology will soon become more valuable in creating new drugs. Already, big pharma companies, including Pfizer, Novartis and GSK, are exploring the potential of iPS cells.

New drugs using iPS cells can be developed mainly in two ways. The first is cultivating iPS cells from disease sufferers to create new cells and tissues, which can be used to find potentially effective treatments based on the disease's progression. The other is creating iPS cells from healthy people, then turning them into heart or liver cells and tissues, for example, and testing potential new drugs on them to check for side effects. Kits for this sort of testing have already been developed and are starting to see use at pharmaceutical companies inside and outside Japan.

Since drug discovery with iPS cells doesn't require testing inside the body, there is no direct risk to a patient's health. Treatments that couldn't be tested before because they might be dangerous will become testable, potentially keeping down costs and shortening development times.

 

Embryonic stem (ES) cells have been known about for longer, but they have raised ethical problems because they are produced from embryos. Even the Pope has expressed his disapproval of their production and use.

Yamanaka's work began as a data-based investigation into why ES cells can change into various kinds of cells, before finally discovering the Yamanaka factors using an experimental method proposed by Takahashi.

A group led by Masayo Takahashi, a project leader at Riken, took the lead in regenerative medicine using iPS cells. In 2014, the group conducted clinical research in which an elderly woman suffering from age-related macular degeneration, the most common cause of permanent blindness, received retinal pigment epithelial cells produced from her own iPS cells. The results of the operation have been good so far. 

While this method of using iPS cells from patients has the advantage of not causing rejection on transplantation, it can take a lot of time -- and it is expensive. The clinical research by Takahashi's group cost about 100 million yen for procedures, including tests to check whether the cells could turn cancerous, and took about 10 months to prepare.

Knowing that the spread of regenerative medicine would be difficult if the costs and speed did not come down, the government hurried to help develop the stock of iPS cells at CiRA. Riken's Takahashi and her collaborators started clinical research in regenerative medicine using cells from the iPS Cell Stock in March 2017. These cells can be used promptly when needed, and costs, including personnel expenses, can probably be reduced by more than 90%, she estimates.

Jun Takahashi, Masayo's husband and a professor at Kyoto University, is working on a regenerative medicine for treating Parkinson's disease using cells from the CiRA stock. He plans to generate cells that produce dopamine, a substance that works as a neurotransmitter, from iPS cells and transplant them in patients. He recently published the results of tests in which human iPS cells were transplanted into a monkey with Parkinson's disease, reducing its symptoms -- including the trembling of its hands and feet. The tests sparked a lot of enthusiasm, and Takahashi hopes to start clinical trials as soon as next year in cooperation with Sumitomo Dainippon Pharma.

Osaka University professor Yoshiki Sawa, president of the Japanese Society for Regenerative Medicine, and other researchers have plans for clinical research for treating heart failure. They plan to produce cardiac muscle cells from iPS cells by layering sheets of them one on top of another, then transplanting them into the hearts of patients with severe heart failure. They plan to conduct the first operation possibly in the first half of 2018.

There are many other plans for clinical applications, including the use of blood platelets for transfusion produced by Kyoto University professor Koji Eto and others and the treatment of liver disease by a Yokohama City University team.

Other countries gain

A key factor in Japan's success was its quick move to streamline its screening and regulatory approval frameworks for new medicines. This prompted the U.S. and Europe to introduce similar systems. But while the Japanese government has funded regenerative medicine studies, support for the development phase that precedes clinical applications is unclear. The public and private sectors have numerous investment plans, but the budgets for these projects are small and the funds are scattered.

"Japan has yet to formulate a strategic road map to nurture regenerative medicine as a growth industry," Toda said. 

The U.K., aiming to bring treatments to patients faster, has established the Cell and Gene Therapy Catapult, which uses private and public funds to build cell-production laboratories and set up collaborative networks among medical institutions. Canada has an industry-government-academia consortium called the Center for Commercialization of Regenerative Medicine.

Japan, where government support for research in fields such as gene therapy is thin compared to that for iPS cells, should emulate other countries and develop a long-term plan that covers various types of cell therapies, Toda says. Aside from a few examples like Takara Bio, there are few corporate initiatives and sparse interest in gene therapy. 

He also insists that there should be common test production facilities co-funded by the government and the private sector to accelerate commercialization of cell products. "If private industry provides the same amount of money as the government and the two sectors work together, they can help accelerate clinical applications," he said.

But Yamanaka, the scientist whose research started the iPS revolution, remains confident.

"Japan leads the world in applications in regenerative medicine," he said. "Things are moving faster than I expected 10 years ago."

Nikkei staff writer Noriaki Koshikawa contributed to this report.

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