Osaka team pulls off cornea cell transplant using human iPS cells

In a world's first, a team of researchers here transplanted cornea cells created from human iPS cells into a patient whose visual acuity has been improved.

The transplant was conducted in July by a team led by Kohji Nishida, a professor of ophthalmology at Osaka University.

The team announced the achievement on Aug. 29 at a news conference at the university's campus in Suita, Osaka Prefecture.

The patient, a woman in her 40s, has made good progress since the operation and was released from the hospital on Aug. 23.

“It’s been just a month, but right now we see the operation as a success,” Nishida said.

The transplant is intended for patients with corneal epithelial stem cell impoverishment syndrome.

The cause of the syndrome is a loss of stem cells that produce a new cornea that can cover the surface of a pupil caused by injury or other reasons. The syndrome leads to poor eyesight and sometimes blindness.

The team transformed iPS cells from a third party into cornea cells. They then turned them into a sheet 0.03 to 0.05 millimeters thick and transplanted them onto the patient’s left eye.

If all goes well, the transplanted cells will enable a lasting production of cornea cells, maintain corneal transparency and help the patient regain lost vision.

“After the operation, her clouded cornea became transparent and her vision has improved considerably. We'll continue to monitor her condition to see if it stays that way," Nishida said.

The team said it has not observed an abnormal increase in the transplanted cornea cells, and the patient has regained vision to the extent that she can go about her daily life.

Following the success, the team expects to perform a second transplant by the end of the year.

Corneas of dead people are currently transplanted into patients with the particular syndrome, but the organs are chronically in short supply.

According to the health ministry, organs from 720 people who were certified brain dead or in cardiac arrest were provided to patients with corneal diseases and 1,155 transplantation surgeries were performed in fiscal 2018.

As of the end of March this year, 1,613 people were on a waiting list for a cornea transplant.

In the team’s estimate, several hundred people in the country each year will become subjects for the cornea transplants using iPS cells.

The operation was the third successful transplant using iPS cells, following the 2014 transplantation of retina cells by the government-affiliated Riken institute and Kyoto University researchers transplanting nerve cells into the brain of a Parkinson’s disease patient in 2018.

Ref: The Asahi PR

Japan approves world-first trial using iPS cells to treat spinal cord injuries

The health ministry approved the world’s first clinical test in which artificially derived stem cells will be used to treat patients with spinal cord injuries.

A team of researchers from Keio University, which filed a request for the test with the ministry, will inject neural cells produced from so-called induced pluripotent stem cells — known as iPS cells — into four people who are injured while playing sports or in traffic accidents.

It is the fifth time the government has authorized clinical studies using iPS cells. The patients, aged 18 or older, will undergo the test treatment under the care of a team led by Hideyuki Okano, a professor at the Keio University School of Medicine.

“It’s been 20 years since I started researching cell treatment. Finally we can start a clinical trial,” Okano said at a news conference in Tokyo. “We want to do our best to establish safety and provide the treatment to patients.”

Okano and his team have already succeeded in enabling a paralyzed monkey to walk again through the same approach.

The patients will have suffered lost mobility and sensation. The cells will be injected within two to four weeks of the patients’ accidents — the period in which the treatment is believed to be effective.

The team will observe the efficacy and safety of the cells for about a year while the patients undergo rehabilitation.

The cells to be transplanted will be created from iPS cells in storage at Kyoto University and will be kept frozen.

Kyoto University’s Shinya Yamanaka won the Nobel Prize in physiology or medicine in 2012 for developing iPS cells, which can grow into any type of body tissue and are seen as a promising tool for regenerative medicine and drug development.

The main purpose of Keio’s study is to confirm the safety of the neural cells to be created. The team will limit the number of cells they will transplant to 2 million but plan to increase that to up to 10 million in the future.

Every year in Japan, around 5,000 people sustain spinal cord damage, and the number of people living with some sort of spinal cord-related injury is estimated to total over 100,000.

People with existing spinal cord injuries are mostly in the chronic phase and, therefore, will not be eligible to the upcoming clinical trial.

But Masaya Nakamura, a Keio professor of orthopedics who is in charge of the procedures, said the team wants to confirm “within two to three years” the safety of the treatment for patients with chronic spinal cord injuries.

A panel at the ministry also reviewed another plan for a clinical test in which corneas produced from iPS cells will be transplanted to treat eye diseases. The trial was proposed by an Osaka University research team. The panel did not reach a decision on the cornea trial, leaving further consideration to future discussions.

Among other clinical tests with iPS cells, the government-backed Riken institute conducted the world’s first transplant of retina cells grown from iPS cells to an individual with an eye disease in 2014.

Kyoto University also began a clinical test using iPS cells to treat Parkinson’s disease last year.

In that test, which took place in October, nerve cells created from iPS cells were transplanted into the brain of a patient in his 50s.

Parkinson’s disease reduces dopamine-producing neurons in the brain, and results in tremors in the hands and feet and stiffness in the body. While there are treatments to relieve the symptoms, there is currently no cure for the disease.

Source: Japan Times 


Kyoto Univ team eyes clinical test of platelets derived from iPS cells
A Kyoto University team plans to begin a clinical test using platelets grown from induced pluripotent stem cells to treat Aplastic anemia, a serious disease, sources with knowledge of the plan said Sunday.

The team led by professor Koji Eto is expected to begin the clinical test after getting approval from the Ministry of Health, Labor and Welfare. The university has already endorsed the plan.

Expectations are high in the field of regenerative medicine for iPS stem cells that can grow into any type of body tissue.

The world's first transplant of retinal cells grown from iPS cells into a patient has already been conducted and research is under way into the application of such cells to treat Parkinson's disease and heart failure.

So far, the team has established a method to produce high-quality platelets -- a key component of blood that can stem bleeding -- in large numbers through the use of iPS cells.

In the envisaged clinical test, the team plans to grow platelets from iPS cells from a patient. They will be injected into the patient to see the safety and effectiveness of the method, according to the sources.

Patients with Aplastic anemia are easy to bleed, get infections, and suffer from headaches as platelets and white blood cells decrease.

Patients with falling numbers of platelets are often treated with blood transfusions. But the patient in the upcoming clinical study has a special immune type and thus the use of platelets derived from the patient's own iPS cells can control rejection, the sources said.

Platelets are used in blood transfusions during surgery and to stem bleeding when people get injured.

Blood donations are one of the most useful ways to secure platelets for use in medical setting. But platelets can be used for a short period of time and ensuring stock is a challenge.

Source: Japan Today 


Japan Announces Physician-initiated clinical trials for Parkinson's disease using iPSCs 

Kyoto University Hospital, in partnership with the Center for iPS Cell Research and Application (CiRA), Kyoto University, has planned physician-initiated clinical trials for Parkinson's disease that transplants dopaminergic progenitors1 generated from induced pluripotent stem (iPS) cells. The clinical trial notification was submitted to the Pharmaceutical and Medical Devices Agency (PMDA; the Japanese equivalent of the FDA) on June 4, 2018, and the clinical trials are scheduled to begin on August 1 this year.

Note: The candidate subjects are required to live in Japan, have Japanese public health insurance and can understand the Japanese informed consent form.

Outline of the Clinical Trials

1. Names

Selected patients will participate in both of the following clinical trials.

a) Kyoto Trial to Evaluate the Safety and Efficacy of iPSC-derived dopaminergic progenitors in the treatment of Parkinson's Disease (Phase I/II)

b) Kyoto Trial to Evaluate the Safety and Efficacy of Tacrolimus2 in the iPSC-based Therapy for Parkinson's Disease (Phase III)

2. Objectives

a) To evaluate the safety and efficacy of transplanting human iPS cell-derived dopaminergic progenitors into the putamen3 of Parkinson's disease patients.

b) To evaluate the safety and efficacy of using tacrolimus for Parkinson's disease patients who received transplantation of human iPS cell-derived dopaminergic progenitors into their putamen.

3. Strategy

Dopaminergic progenitors are generated from iPS cells prepared at the iPS Cell Stock for Regenerative Medicine4 at CiRA and then transplanted into the bilateral putamen of seven subjects (Parkinson's disease patients) at the Kyoto University Hospital.

The source iPS cells were generated from third-party donor blood cells, meaning the transplantations will be allogeneic. Because of a possible transplant rejection, patients will receive a standard immunosuppressant, tacrolimus. Each subject will be observed for two years post transplantation.

4. The cell transplantation surgeryApproximately 5 million iPS cell-derived dopaminergic progenitors will be transplanted by stereotaxic brain surgery5 into the left and right sides of the patient's putamen.


1)Dopaminergic progenitorsDopaminergic neurons produce the neurotransmitter dopamine. In Parkinson's disease, these cells degenerate, resulting in decreased dopamine production. Dopaminergic progenitors differentiate into dopaminergic neurons. Animal studies have shown that transplanted progenitor cells will differentiate into mature dopaminergic neurons, resulting in efficient engraftment in the brain.

2)TacrolimusAn immunosuppressant commonly used following organ transplantation.

3)PutamenA region in the basal ganglia that is innervated by midbrain dopaminergic neurons.

4)iPS Cell Stock for Regenerative MedicineClinical-grade iPS cells are generated from healthy donors with specific cell types (HLA homozygosity) that are less likely to cause immune rejection in many people, and are stockpiled at CiRA following thorough quality check.

5)Stereotaxic brain surgeryThis neurosurgery involves drilling small holes on the patient's skull, through which a needle is entered or electrodes are embedded. One of the current therapies for Parkinson's disease, deep brain stimulation (DBS) surgery, is a type of the stereotaxic brain surgery.

Sources: CiRA PR

Interview with Jun Takahashi regarding this program via @RegMedNet: "Preparing for first human trial of iPSC-derived cells for Parkinson’s disease"


Japan approves clinical trials of stem cell treatment for Parkinson's disease - Kyoto University to conduct first-ever iPS-based test for incurable disease 

KYOTO (Kyodo) -- A Kyoto University research team said Monday it will begin this week a clinical test using induced pluripotent stem cells to treat Parkinson's disease, in what will be the world's first application of iPS to the progressive neurological disorder.

The team led by Jun Takahashi, a professor at the university's Center for iPS Cell Research and Application, has received government approval and is soliciting several patients to participate in the trial to be conducted at Kyoto University Hospital, according to sources close to the matter.

The team is scheduled to hold a press conference to explain the details of the clinical test later in the day.

Parkinson's disease reduces dopamine-producing neurons in the brain and results in tremors in the hands and feet, and stiffness in the body. While there are treatments to relieve the symptoms, there is currently no cure for the disease.

In the clinical test that will start on Wednesday, nerve cells derived from other people and stored at the university will be transplanted into the brains of patients to supplement damaged nerve cells.The team has already tested the process on monkeys in a preclinical study, in which the movement of the affected animals improved without seeing any tumors that could develop into cancer in the brain over a two-year observation period.

The clinical trial will be led by doctors who will determine the safety and effectiveness of the test.Among other clinical tests of iPS cells, the government-backed Riken institute conducted the world's first transplant of retinal cells grown from iPS cells to a patient suffering from a serious disease in 2014.

Osaka University is also planning a clinical test for treating heart failure by using a heart muscle cell sheet created from iPS cells.

Source: Nikkei Asian Review

Channel News Asia Coverage of Pakinson's iPSC Trial Topic


iPSC Platelet Program Advancing

Megakaryon of Japan is steadily moving forward to pioneer the world's first clinical trial of stem cell generated Platelets with a novel scale-up technology.

Turbulence is good for the blood
The Koji Eto lab shows that turbulence enhances the production of platelets


Blood flows through the body smoothly in order to transport its content throughout the body. In a new study seen in Cell, scientists at CiRA show unexpectedly that small levels of turbulence in the blood promotes the generation of platelets, the cells responsible for wound healing. Using this new information, they report a bioreactor that produces more than 100 billion platelets from iPS cells, a number that can be used to treat patients.

Blood transfusions are the oldest form of cell therapy and have been done for centuries. Platelets are blood cells that stop bleeding and have other healing factors. Platelet transfusions are common for patients undergoing surgery, cancer therapies, or suffering from platelet-related diseases. However, platelets taken from donors can only be stored for several days, which is why organizations like the Red Cross hold regular blood drives. While this approach is the global standard, with the number of aging populations increasing, many nations are anticipating severe donor shortages. Japan alone estimates that its platelet supplies will serve only four of every five patients in the next decade.

CiRA Professor Koji Eto, who is also Professor at the Chiba University School of Medicine, has been developing platelets using iPS cell technology to replace the dependency on donors. Platelets are extremely small fragments that blood flow breaks off the surface of much larger cells called megakaryocytes, much like washing debris off a car. Unlike platelets, megakaryocytes can be stored for long periods, but they are extremely rare in the body and therefore difficult to acquire from donors. Eto's research team has found a solution to this problem by making an almost unlimited supply of megakaryocytes from iPS cells.

To produce platelets from megakaryocytes, engineers constructed bioreactors that recapitulate blood flow. However, for regular patient care, more than 100 billion-order platelets are needed, and no bioreactor comes close to producing this amount.

"There has been lots of work on bioreactors, but they only used laminar flow. Nobody thought about turbulence," said Eto.

To reach the numbers needed for patient therapy, the new study shows that besides laminar flow, incorporating turbulent flow into the bioreactors is key.

This realization came from microscopic observations of blood flow in mice. While the blood flow was mostly laminar, Eto's team found turbulence was present around the megakaryocytes.

To generate turbulence, their new bioreactor behaves like a French Press coffee maker, pushing the flow up and down.

Further study revealed that the turbulence stimulates three mediators: macrophage migration inhibitory factor, insulin growth factor binding protein 2, and nardilysin, all of which were previously unknown to have a crucial role in platelet generation.

Dr. Naoshi Sugimoto, a hematologist and member of the lab who contributed to the study said, "we can use the mediators to make a specialized culture to improve the performance of the bioreactor."

Finally, the platelets were found to behave normally in mouse and rabbits, an important final step before using them in humans.

"Our goal is to produce platelets in the lab to replace human donors," said Eto.


The paper "Turbulence Activates Platelet Biogenesis to Enable Clinical Scale Ex Vivo Production" in Cell with doi: 10.1016/j.cell.2018.06.011

About Center for iPS Cell Research and Application (CiRA)

CiRA was founded in 2008 and is devoted to the study of induced pluripotent stem cells (iPS cells) and other forms of cell reprogramming along with their medical applications. Since its inception, CiRA has been directed by Shinya Yamanaka, who earned the Nobel Prize in 2012 for his discovery of induced pluripotent stem cells (iPS cells). For more information, please see: https://www.cira.kyoto-u.ac.jp/e/index.html

Kyoto University is one of Japan and Asia's premier research institutions, founded in 1897 and responsible for producing numerous Nobel laureates and winners of other prestigious international prizes. A broad curriculum across the arts and sciences at both undergraduate and graduate levels is complemented by numerous research centers, as well as facilities and offices around Japan and the world. For more information please see: http://www.kyoto-u.ac.jp/en

Source here


First-ever trial of drug using iPS cells to begin at Kyoto University

Kyoto University researchers are set to begin the world’s first clinical trial of a drug identified using iPS cells to treat a rare bone disease, the university said Tuesday.

A team led by Junya Toguchida, a professor at the university, used induced pluripotent stem cells to develop a potential drug for fibrodysplasia ossificans progressiva (FOP), a rare disorder in which muscle tissue is gradually replaced by bone, inhibiting body movement.

The researchers created iPS cells from FOP patients and replicated the symptom outside their bodies. After adding components to the cells with features of the disease, they found that — out of 6,800 substances — an immune-suppressive agent called Rapamycin was effective for preventing abnormal bone formation.

The drug’s safety and effectiveness need to be tested in a clinical trial, which could begin as early as September, on 20 patients aged 6 or older. A review committee at Kyoto University Hospital has already approved the trial.

The team has confirmed the effectiveness of Rapamycin in experiments with mice. Researchers gave the agent to mice after transplanting FOP patients’ iPS cells into them, and found that the drug inhibited abnormal bone formation. “Rapamycin is a drug already used (for treatment of other diseases) so I expect patients will happily accept it” in the clinical trial, Toguchida said at a news conference in Kyoto crowded with dozens of reporters and several television cameras — reflecting the strong interest in the clinical trial.

“It’s taken us a long time to get here,” Toguchida said, adding that there are currently around 80 FOP patients in Japan.

He said many of the patients have studied their symptoms and have a scientific understanding of the disorder. Makoto Ikeya, an associate professor and a member of the team, said he hoped the new trial will give FOP patients hope.

Shinya Yamanaka, professor at Kyoto University and a 2012 Nobel Prize winner in medicine for discovering iPS cells, said, “I hope the clinical trial will spur active research for drug development, and eventually lead to the discoveries of new treatment for various rare diseases.”

FOP is caused by a mutation of the ACVR1 gene. Bones are formed in muscles, tendons and ligaments, hindering the movements of joints.

Any type of human body tissue can be formed using iPS cells. They are expected to be utilized for drug development as well as regenerative medicine.

Source: The Japan Times - Also see The Mainichi article on the topic here


Japan is set to host the world's first clinical trials involving the use of induced pluripotent stem (iPS) cells to treat heart failure. 

A special health ministry panel on Wednesday gave Osaka University the green light to carry out the study, pending final authorization from the health minister. This would be the second instance of using iPS-derived cells for disease treatment in Japan, after groundbreaking trials involving retinal cells launched in 2014.

Heart failure is the country's No. 2 cause of death. The research team, led by Osaka University professor Yoshiki Sawa, aims to start treating patients on a wider basis in five years. 

Before that, the trial treatment will be administered to three patients suffering from ischemic cardiomyopathy, a serious condition that occurs when narrowed coronary arteries limit the supply of blood to the heart. The plan is to start the trials by the end of next March and spend a year examining the effects and potential safety issues. 

The researchers will grow cardio muscle cells created from iPS cells stocked at the Center for iPS Cell Research and Application at Kyoto University, where Nobel laureate Shinya Yamanaka serves as director. The created cells, in the form of 0.1 millimeter-thick sheets, will be layered onto the surface of the patient's heart. As the sheets secrete protein, the nutrition is expected to help grow blood vessels and improve heart functions.

Heart failure causes symptoms such as shortness of breath and fatigue. In serious cases, patients require an auxiliary artificial heart, or a heart transplant from a donor. Neither option is ideal: Artificial hearts come with the risk of complications, and there are not enough donors.

The iPS-based treatment could offer a way around those limitations.

Sawa's team submitted its plan to the Ministry of Health, Labor and Welfare in March. The panel, including regenerative medicine experts, approved it on the condition that trial patients should be chosen with the same criteria used for regenerative treatments already on the market.

Source: Asian Review

First serious adverse reaction to iPS-derived retinal cell transplant reported

KOBE – A patient who underwent transplant surgery using retinal cells derived from so-called iPS cells from another person has suffered a swollen retina, the team that carried out the world’s first clinical trial of the procedure said Tuesday.

It is the first time a patient has developed a serious adverse reaction during the clinical research to assess the feasibility of using the artificially derived induced pluripotent stem cells, said the researchers from Kobe City Medical Center General Hospital and the government-backed Riken institute.
Doctors operated on the patient in his 70s on Monday to remove pre-retinal membrane, deemed to be the cause of the retinal edema. The team was unable to improve the symptoms despite the administration of steroid and anti-vascular endothelial growth factor medication.
“We cannot deny the causal correlation with iPS cells,” Masayo Takahashi, a researcher at Riken who heads the team, said at a news conference.
Takahashi said the symptom “falls into the category of serious cases,” as it requires hospital admission for treatment, but stressed that it is “neither a matter of great urgency nor life-threatening.”
She said the incident most likely will not affect future clinical studies on the transplantation of iPS-derived retinal cells in patients with severe eye diseases.
The patient underwent the transplant in June to treat exudative age-related macular degeneration, a vision-threatening disease, at the hospital in Kobe. It was the second such transplant of iPS-derived cells. His condition improved after the removal of pre-retinal membrane, the team said.
The team believes the edema was caused by a reverse in the flow of a liquid solution containing retinal cells derived from iPS cells. The development of edema does not signify a rejection of iPS cells or its side-effects and there is room for improvement in the prevention of the backward flow, the team said.
In regard to the clinical study, the team conducted the first such transplant surgery on a man from Hyogo Prefecture in March. In November, it announced the completion of all five planned procedures.
All of the operations were conducted using iPS cells kept at Kyoto University, which were created to avoid strong immune system reactions.
“This case is not so serious. As long as the pre-retinal membrane is removed during surgery, there would not be a significant problem,” said Noriyuki Azuma, chief of the visual science laboratory at the National Center for Child Health and Development.
“(This case) would not put a stop to regenerative medical techniques,” he said, adding that it would be important to thoroughly check the pre-retinal membrane taken from the patient to find the cause of the adverse reaction.
The research team made the announcement in accordance with a law requiring that medical institutions report to the Minister of Health, Labor and Welfare if a patient’s illness or worsening condition is suspected to have been caused by regenerative medical techniques that the person underwent.


Japanese man is first to receive 'reprogrammed' stem cells from another person

World-first transplant to treat macular degeneration could augur rise of iPS cell banks


Interview with Masayo Takahashi of RIKEN re: iPS Trial

Speaking with Masayo Takahashi: Targeting age-related macular degeneration in the first iPSC clinical trial

Go to the profile of Freya Leask Credit: Freya Leask - @RegMedNet - Original Article 
In this interview, Masayo Takahashi, Project Leader for Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology (Kobe, Japan) explains the techniques being utilized in the first induced pluripotent stem cell (iPSC) clinical trial in humans. Dr Takahashi also reveals how they may change when the trial restarts, having been halted in 2015.
Masayo Takahashi (MD, PhD)
Masayo Takahashi MD, PhD is Project Leader of the Laboratory for Retinal Regeneration at RIKEN (Kobe, Japan). She received her MD from Kyoto University (Kyoto, Japan) in 1986, and her PhD in Medicine at the same institution in 1992. After serving as an assistant professor in the Department of Ophthalmology, Kyoto University Hospital, she moved to the Salk Institute (CA, USA) in 1995, where she first learned of the potential of stem cells as a tool for retinal therapy. She returned to the same hospital in 1997, and since 2001 has served as an associate professor at the Translational Research Center (Kyoto, Japan). She joined RIKEN as a team leader of the retinal regeneration team in 2006. Her team started a pilot clinical study of autologous iPS cell-derived RPE cell sheets for exudative aged-related macular degeneration in 2013. The first RPE cell sheet graft was transplanted in September 2014.

Why did you choose age-related macular degeneration as the target for the iPSC therapy?

My research using stem cells began in 1995 and I have been trying to develop a therapy ever since. I researched embryonic stem cells (ESCs) and finally came to study iPSCs. From iPSCs, we can develop different retinal cells, including retinal pigment epithelial (RPE) cells and photoreceptor cells, and we are currently working on a therapy using both of these. However, photoreceptor cells are neurons so it can be difficult to make them work in the body, whereas RPE cells are not so it is easier to develop treatment. We found that RPE cells were most effective in treating age-related macular degeneration, which afflicts many people, so this is the target we chose first. [Ed: A study published in the Lancet in 2014 estimated that 196 million people will suffer from either dry- or wet-type age-related macular degeneration, rising to 288 million in 20401.]

What challenges have you faced in planning and executing the trial?

It’s very difficult to make and maintain good iPSCs, but we have very talented technicians who can make good iPSCs and culture them properly. In the first trial, we made 30 lines of iPSCs from one patient then selected the good iPSCs. The purity of the end product is also very important; there should be no bad cell contamination.

What techniques did you utilize to select the good iPSCs?

We chose the best cell lines by looking at their morphology first. Our technicians are very experienced so by looking at characteristics such as the colors, the smoothness of the cell surface and the dividing speed, they can tell which cells are good and bad. We then confirmed that the cells were good using gene analysis.

In 2015, the trial was halted. What happened, and will any changes be made to the trial design when it starts up again?

The first clinical research was halted because the law for regenerative medicine in Japan changed, but we’re now preparing the next clinical study. We will use three different protocols including allogeneic iPSCs. In the first trial, we used only autologous iPSCs, but next time we will use both. We won’t use immunosuppressive drugs, which is a big challenge when using allogeneic cells, but we will utilize human leukocyte antigen (HLA) typing to minimize any problems this may cause.

What does the future hold for iPSC therapy?

I think it’s very promising. Without a doubt, regenerative medicine will become a big field in the future. In fact, preventative and regenerative medicine will be two big fields, and iPSCs and ESCs have the potential to industrialize the cell therapy field. iPSCs and ESCs can be expanded so we can make many cells for many patients and really build regenerative medicine as an industry.


  •     Research fund from Healios K.K. and Sumitomo Dainippon Pharma Co., Ltd.


  1. Update article on approval of Allo iPSC cells for human application

RIKEN to resume retinal iPS transplant

KOBE (Jiji Press) — The government-affiliated research institute RIKEN said Monday that it will resume its clinical study in which retinal tissues developed from iPS cells will be transplanted in an eye disease patient, in cooperation with Kyoto University and other medical institutes.

In 2014, the RIKEN Center for Developmental Biology, or CDB, successfully conducted a retinal transplant using induced pluripotent stem cells for the first time in the world. But its second trial was suspended due to a gene abnormality found in iPS cells.

In the first trial, iPS cells were created from cells taken from the patient who underwent the transplant.

Next time, the study team, led by Masayo Takahashi, project leader at the CDB, plans to use iPS cells created from mature cells of some others, since the first operation proved using a patient’s own cells is time-consuming and costly.

For the second trial, the CDB will develop retinal tissues from iPS cells supplied by Kyoto University’s Center for iPS Cell Research and Application, headed by Nobel laureate Shinya Yamanaka, the creator of the pluripotent cells.

Transplants of CDB-developed retinal tissues will be conducted at Kobe City Medical Center General Hospital and Osaka University Hospital.

The four institutes have signed an agreement to strengthen their collaboration. The partnership is “encouraging,” Takahashi said at a press conference on Monday. She expressed eagerness to carry out the next operation early next year.

Yamanaka said at the same news conference the he was heartened by the four institutes teaming up to push the study forward.

Credits: The Japan News by The Yomiuri Shimbun / Jiji Press


The Quest for Advanced Regenerative Medicine
Foreign Firms Drawn by Japan’s Expedited Approval System

Regenerative medicine is drawing attention as a form of treatment using people’s cells and a method that can be used for testing new pharmaceuticals. Japan has been leading the world in this field, as exemplified by the research into induced pluripotent stem cells (iPS cells) by Dr. Shinya Yamanaka, winner of the 2012 Nobel Prize in Physiology or Medicine. The global market for regenerative medicine is seen as growing to a huge JPY 38 trillion (USD 345 billion) by 2050. In Japan, government and industry are working hand in hand to advance this field with measures including bold regulatory reform and active promotion of investment by foreign corporations.

In November 2014 Japan became the first country in the world to adopt an expedited approval system for regenerative medical products and to allow outsourced cell culturing. Two products were approved under the new system within a year of its adoption. Thanks to this system, it has become possible in some cases to secure approval of new regenerative medical products in Japan prior to their approval in other countries.

In 2015 three government ministries—the Ministry of Education, Culture, Sports, Science and Technology; the Ministry of Health, Labour and Welfare; and the Ministry of Economy, Trade and Industry—joined in establishing the Japan Agency for Medical Research and Development. Through this agency the three ministries have created a unified setup for promotion of research and development. Meanwhile, the Japan External Trade Organization (JETRO) has taken the lead in efforts to support foreign companies that invest in regenerative medicine in Japan, with some JPY 1 billion (USD 9 million) in financial support available. Thanks to such initiatives, foreign companies have come to see Japan’s regenerative medicine market as offering opportunities.

Japanese industry is also welcoming the entry of foreign participants. As early as 2011, companies involved in this field joined in launching the Forum for Innovative Regenerative Medicine (FIRM) to serve as a pipe connecting the relevant companies and research institutions, both Japanese and foreign. FIRM’s Representative Director and Chairman Yuzo Toda stresses, “Japan, with its aging population, has a strong need for regenerative medicine, and it also has the technological strength to develop practical applications based on research results.”

According to FIRM, some foreign companies are now considering making Japan the initial market for their new regenerative medical products so as to achieve quick practical use for them. Toda declares, “Conditions are in place for realization of Japan-made, world- first products. FIRM’s role is to serve as an incubator for the regenerative medicine industry. We want to advance initiatives to open up this new field, working in tandem with Japanese and foreign companies.”

FIRM has established a partnership with the Alliance for Regenerative Medicine (ARM), America’s trade association for regenerative medicine. It also has tie-ups with Sweden, Britain, and Australia, and Canada will soon join the list. Japan’s initiatives in the field of regenerative medicine are developing international breadth.

Forum for Innovative Regenerative Medicine official website

Global scale of the regenerative medicine market

The future scale of the global market for regenerative medicine is forecast to grow to JPY 1 trillion (USD 9 billion) by 2020 and JPY 38 trillion (USD 345 billion) by 2050.

A medical field drawing global attention

Examples of regenerative medicine using iPS cells, embryonic stem cells, and somatic stem cells, now drawing attention for its potential in curing previously untreatable conditions.

Shortening of development period under expedited approval system
By comparison with the previous approval process, this system provides for a major shortening of the time required for approval of pharmaceuticals, subject to further confirmation after marketing, followed by a review of the approval.

Two regenerative medical products approved
Yuzo Toda, Representative Director, Chairman
Forum for Innovative Regenerative Medicine (FIRM)
FIRM, with 185 corporate members as of January 2016, is working to close gaps in awareness and regulations regarding regenerative medicine among industry, academia, government, and citizens, as well as to show specific ways forward.

Authorized copy source:  Japan Gov Source Link

Masayo Takahashi - "Hope - Yes" & "Patients First"

During ISSCR 2015 I had the opportunity to sit down with Masayo Takahashi of Riken. The interview can be found here and is an update to the below information on the first in human iPS clinical trial for Wet AMD. 

Paul Knoepfler ran the interview and also provided a background story on the regulatory pause in Japan on the trial pending review of the data & application to move forward using a different cell source.


Masayo Takahashi: Leader of First Ever In-human Clinical Study Using iPS cells

Masayo Takahashi – Regenerative Medicine Using iPS Cells

RIKEN's iPS RPE cell sheet science for the Eye is being commercially developed by an arm's length technology Licensee, Healios. To-date the company has secured a number of important program partners and funding to establish a vertically integrated operation for global product marketing. Part of the strategy is to align the technology in international market regions - such as Europe and the US. Manufacturing and scientific collaborations are being established and structured to ensure strength (such as with UCL in the UK).  

“Healios is seeking conditional approval for HLCR011 under newly established regulations for conditional and temporary approval (“conditional approval”) for cellular and tissue-based products (Article 23 and Article 26, Clause 1 of the revised [Japanese] Pharmaceutical Affairs Law)” https://www.healios.co.jp/en/development/pipeline/

"Healios entered into a joint development agreement with Sumitomo Dainippon Pharma Co., Ltd. in 2013. Under the agreement, Sumitomo Dainippon Pharma provides funds to Healios for co-developing iPS cell–derived human retinal pigment epithelial (RPE) cells and obtaining approval for the manufacture and sales of such products. Additionally, our two companies established a joint venture, SighRegen, in 2014 to promote the manufacture and sales of commercialized RPE cell products.

Healios is also working with Shibuya Kogyo CO., LTD., Nikon Corporation and Osaka University on the development of an automated culturing device with a view towards greater manufacturing efficiency. In such ways, we are building a strong development ecosystem and value chain so that we can promote the practical application of iPSC regenerative medicine products.

We are also planning for Healios-led development outside Japan. To date, we have completed the selection of manufacturing subcontractors in the US and European markets. We have also embarked on technology transfers to those subcontractors, and are in consultations with US regulatory authorities." https://www.healios.co.jp/en/development/

Riken will tap iPS cell bank for transplant NIKKEI Asian Review - March 21, 2015

OSAKA -- "A stockpile of stem cells derived from other people will be used in clinical trials of cell transplants for patients with an incurable eye disease, a potential breakthrough that could sharply reduce costs and waiting time.

Masayo Takahashi of the government-affiliated Riken research institute announced the plan Friday. Under a project led by her, a patient with age-related macular degeneration received a transplant of cell sheets made from induced pluripotent stem cells, or iPS cells, in September. The iPS cells were created from the patient's own cells to avoid transplant rejection.

For the second trial, slated to take place as early as 2017, iPS cells derived from other people will be used. While the first method is believed to have cost 50 million yen to 100 million yen ($410,600 to $821,300), Takahashi said that using stockpiled cells could reduce the cost to less than 10 million yen. And preparation time would be shortened from nearly one year to about six months.

"From a stock of iPS cells from one person, we can cultivate enough cells to transplant to dozens of patients," Takahashi said.

Kyoto University and others working to prepare a frozen stockpile of iPS cells for distribution will choose donors with special physical attributes unlikely to cause rejection.

Experiments on monkeys have yielded promising results. Little or no medication to curb rejection may be needed.

The iPS cell bank, with thorough control of safety and quality, is expected to help clear many hurdles to making regenerative medicine using stem cells accessible."

(Nikkei Article)

Foundation for Biomedical Research and Innovation RIKEN Press Release - September 12, 2014 

First RPE cell sheet graft transplant

"Today, the first participant in the “Clinical study of autologous induced pluripotent stem cell-derived retinal pigment epithelium (RPE) cell sheets for exudative age-related macular degeneration (AMD)” underwent transplantation of a cell sheet graft. Surgical schedule Location: Institute for Biomedical Research and Innovation (Kobe, Japan) Start of procedure: 14:20, September 12, 2014 End of procedure: 16:20, September 12, 2014 Surgical staff: A team led by Yasuo Kurimoto, M.D. and two other ophthalmologists. Result A single RPE cell sheet (1.3 mm × 3 mm) was engrafted into the subretinal space of one eye. There was no serious hemorrhaging or complications. Research subject Residence: Hyogo Prefecture Age: 70s Gender: Female To protect patient confidentiality, and out of respect for the strong wishes of the individual, no information other than that given above will be made public. Research funding This clinical study is funded by the Japan Science and Technology Agency and the Ministry of Health, Labour and Welfare." http://www.riken-ibri.jp/AMD/img/20140912_1en.pdf

Project Summary 
Clinical Research: 

Testing for safety and efficacy is required before any new medical intervention can enter routine use. Such clinical research takes various forms that differ in the number of human research subjects and features of the study design. In Japanese law, two main types of clinical experiments are recognized: registered clinical trials, which are used to test medical products prior to market authorization, and general clinical research, which includes smaller-scale studies, such as the pilot study described [...], and evaluations of some medical procedures, such as surgical techniques.

The research plan introduced [...] is for an open-label study of the transplantation of autologous induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) cell sheets in patients with exudative age-related macular degeneration (AMD). This is a very early-stage form of clinical research, and is intended to assess the safety of this intervention; it is not expected to yield significant improvements in visual acuity or other symptoms in the patients who participate in the study.

Important Points: 

1) The current study is designed to evaluate this intervention only in patients with the exudative (wet-type) form of age-related macular degeneration.

2) The primary outcome to be assessed in this study is the safety of the intervention. If it is found to be acceptably safe, future studies will evaluate its efficacy. Patients who participate in this pilot study are not expected to experience dramatic improvements in their symptoms.

3) Enrollment in the study is limited to six subjects, as the safety of the intervention has not been established.

4) This pilot study is a very early stage of clinical research into the use of an iPSC-based intervention. Even in the event that this study suggests the intervention is acceptably safe to proceed to subsequent stages, a great deal of further research, including full-scale clinical trials, will be needed to more thoroughly evaluate the safety and efficacy of this approach.

Generation and Transplantation of RPE Cell Sheets:

In the first stage of the study, a 4 mm biopsy of tissue will be collected from the skin of each subject’s upper arm and cultured in a cell processing center. The skin cells will then be used to generate induced pluripotent stem cells (iPSCs). The autologous iPSCs will next be differentiated in culture into monolayer ‘sheets’ of retinal pigment epithelium (RPE) suitable for transplantation. The entire process, including regular assessments of safety and quality, will require approximately 10 months for each patient.


Once complete, the RPE cell sheets will be transplanted into the affected site in a single eye, from which the neovascular tissue has first been removed. Subjects will be monitored and followed up for four years following transplantation.

Potential Risks and Benefits: 

The primary goal of this pilot study is to evaluate the safety of the transplantation of autologous induced pluripotent stem cell (iPSC)-derived retinal pigment epithelium (RPE) cell sheets in patients with exudative age-related macular degeneration (AMD). Patients who participate in this study are not expected to experience dramatic improvements in visual acuity or other symptoms. In the event that the intervention is found to be acceptably safe in this small group of patients, much additional research will be needed to evaluate its safety and efficacy in larger numbers of patients.

This is a first-in-human study using RPE cells differentiated from a pluripotent stem cell source. While intensive preclinical research in cultured cells and animal models has been conducted, it is impossible to rule out the risk of tumor formation triggered by the transplanted cells. The harvesting of tissue from the arm to be used for generation of iPSCs is an invasive procedure and will be conducted under anesthesia, both of which are associated with some risk, and the transplantation procedure is associated with risks including bleeding, infection, retinal detachment, any of which can lead to loss of visual function. The physicians conducting the study will monitor closely for any such adverse events, and take all appropriate measures should an adverse event occur.


After obtaining informed consent, volunteers will be screened for eligibility to participate in the study following a number of predefined inclusion and exclusion criteria – those selected will be enrolled in the ‘primary registration’ for the study. After primary enrollment, skin samples will be harvested from each patient and used to generate autologous iPSC-derived RPE cell sheets, a process that will take approximately 10 months.

After safety and quality testing, the RPE cell sheet will be prepared for transplantation. The terms of the original informed consent document will be reconfirmed with each subject, and providing the subject’s consent remains unchanged, he or she will be enrolled in the ‘secondary registration’ prior to transplantation. All patients will be intensively monitored for one year, with additional follow-up for three years following transplantation of the RPE cell sheet.

Post-Transplant Monitoring:

All subjects will be monitored intensively for the first year following the transplantation of the RPE cell sheet, with monthly evaluations for the first 6 months and bimonthly evaluations for the next 6 months. These evaluations will include tests of visual function, intraocular pressure, and medical imaging. Data from these examinations will be compiled and analyzed to evaluate the safety of the intervention and any effects on visual function. During the 3-year follow-up period, subjects will have annual eye examinations. Comprehensive cancer screening will be conducted at the harvesting of the skin biopsy, prior to the transplantation of the RPE cell sheet, at one year post-transplant, and at the end of the follow-up period (4 years post-transplant). Following this 4-year post-transplant monitoring and follow-up period, additional long-term observation of the study subjects will be periodically conducted.
Partner organizations

This pilot study is a joint clinical research project coordinated and conducted by RIKEN, the IBRI (Institute for Biomedical Research and Innovation) Hospital, and the Kobe City Medical Center General Hospital. The IBRI Hospital will harvest skin biopsies, transplant RPE cell sheets, and conduct pre- and post-transplant monitoring of subjects. RIKEN will generate autologous iPSCs from the subjects’ skin cells and differentiate the iPSCs into RPE cell sheets. Kobe City Medical Center General Hospital will conduct some of the examinations during the monitoring period, support the screening process and, if necessary, provide emergency medical services.

Disease Indication:

The organizations involved in the current pilot study are urgently working to develop safe and effective treatments for age-related macular degeneration. This study is only the first step of many that will be needed to determine whether this transplantation of autologous iPSC-derived RPE cell sheets will be appropriate for use in the treatment of this disease. Due to the preliminary nature and small size of the study, the requirement for intensive long-term monitoring, the possible need for rapid access to emergency medical treatment, and the importance of clear communications with research and medical staff, including documentation required for the study, enrollment will be limited in principle to residents of Japan. The results of the study will be published as soon as they are available, and if they support the preliminary safety of this approach, may lead additional larger-scale research and development efforts in Japan and other countries.

About AMD - Retinal Pigment Epithelium

The macula is the central region of the retina and plays important roles in light-sensing and visual acuity. The retina is made of up a sensory retina layer that contains a type of neurons known as photoreceptors that convert light signals into neural activity and a supporting layer of non-neural cells called retinal pigment epithelium (RPE). The RPE acts as a barrier that separates the eye from the rest of the body, absorbs cellular waste materials, and also serves as a source of molecules called trophic factors that are needed for the survival and function of other nearby cells. Damage to the RPE can thus also affect the function of the sensory retina.

Age-related Macular Degeneration:

In age-related macular degeneration (AMD), the function of the macula deteriorates with age, which can be due to a number of causes. In the neovascular or exudative form of AMD (often called ‘wet-type AMD’), abnormal growth of new blood vessels occurs in the region immediately next to the eye (a process known as choroidal neovascularization). These new blood vessels may leak serum or blood and invade the overlying tissue, causing damage to the RPE and sensory retina.

The early symptoms of AMD include loss of acuity and contrast sensitivity in the center of the visual field, object distortion, blurring, and dimness of vision. In some cases, the onset of symptoms is rapid. As AMD increases in severity, it can lead to retinal detachment or hemorrhage, which can cause loss of vision in other parts of the eye as well.

Causes of AMD:

The precise cause of AMD remains unknown, but aging, inflammation, and genetic factors are believed to play roles in weakening of the RPE. A second form of the disease, atrophic (or dry-type) AMD, is prevalent in people of European descent, while the wet-type is more common in Japan and other parts of East Asia. In Japan, around 1% of all people aged 50 and older suffer from some form of AMD.

Current treatments:

Most current forms of treatment for wet-type AMD focus on stopping the abnormal blood vessel growth known as choroidal neovascularization, with the goal of preventing further progression of the disease. If neovascularization is absent in the fovea (the center of the macula), a laser can be used to ablate the blood vessels, while in cases of foveal neovascularization, agents that inhibit the activity of VEGF, a molecule that promotes the formation of blood vessels, have been approved for use. However, such treatments only prevent the progression of the disease, and cannot repair tissue damage that has already occurred to the RPE or sensory retina. Thus, therapies that both halt the growth of new blood vessels and reconstruct damaged tissue are needed to fully treat the effects of this disease.

RIKEN CDB 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan
Foundation for Biomedical Research and Innovation 
2-2 Minatojima-minamimachi ,Chuo-ku, Kobe 650-0047, Japan
Copyright 2013 RIKEN-Foundation for Biomedical Research and Innovation. All rights reserved.

Publications & Research Lab Links:
Masayo Takahashi (M.D., Ph.D.) Lab - Riken Center for Developmental Biology

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