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Highway Program for Realization of Regenerative Medicine


Field "A"
Projects targeting clinical study in the short term

First Year FY2012
Title Bone and cartilage regeneration using magnetic targeting system of magnetically labeled bone marrow mesenchymal cells
Principal Investigator Mitsuo Ochi
(Professor, Graduate School of Biomedical and Health Sciences, Hiroshima University)
Subsidiary institution Japan Tissue Engineering Co., Ltd.
Summary The aim of this research is to establish minimal invasive and highly effective cell transplantation methods for treating articular cartilage defect and refractory fractures.
Joint diseases and fractures are put forward as the principal factors resulting in nursing care requirements for elderly patients, and, with the aging of Japanese society, prevention and treatment of these conditions are increasingly important issues in Japanese medicine.
In this research, the aims are to develop a technique, magnetic targeting, using magnetically labeled bone marrow mesenchymal cells, by which cells are controlled from outside the body by means of an external magnetic field, so that the transplanted cells accumulate at the site of injury; and to establish minimal invasive and highly effective treatment methods. The targets are to carry out research relating to the quality and safety evaluation of magnetically labeled bone marrow mesenchymal cells required for initiation of clinical research, to submit the clinical research schedule applicable to “Policies for clinical research using human stem cells” in 2014, and then to obtain approval, and initiate clinical research.
First Year FY2011
Title Development of methods for treating age-related macular degeneration by transplantation of retinal pigment epithelial (RPE) cells derived from induced pluripotent stem (iPS) cells
Principal Investigator Masayo Takahashi
(Project Leader, Center for Developmental Biology, RIKEN)
Subsidiary institution Foundation for Biomedical Research and Innovation
Summary Exudative age-related macular degeneration is caused by aging of RPE cells, and choroidal neovascularization leads to severe decrease in visual acuity. Treatment with antineovascularization agents (anti-VEGF formulations) is effective to some degree, but RPE damage cannot be treated, and regenerative medicine, involving cell transplantation, is therefore needed for radical therapy. However, RPE cell allotransplantation is known to induce rejection reactions. The availability of iPS cells has made feasible a type of fundamental treatment for age-related macular degeneration due to RPE aging, in which the subretinal neovascular membrane is removed surgically, and the lost or damaged RPE is then replaced with young RPE prepared from the patient’s own cells.
With respect to previous research, in animal experiments it was found to be possible to ensure the quality and quantity of iPS-cell-derived RPE cells that elicit functions in vivo, but these could not be used in clinical research without modification. For all processes, it has been found necessary to change, in accordance with good manufacturing practice, the materials used to items that are clinically usable. In addition, in order to obtain cells for clinical use, it is necessary to prepare them in a cell-processing center, where the environment is controlled. Furthermore, quality-control specifications enabling preparation of cell sheets that are of similar quality on each occasion must be defined and verified, and in clinical research using iPS cells the most important aspects of safety must be ensured. RPE cells have characteristic functions, including photoreceptor outer segment phagocytosis, and secretion of various growth factors, and when these were quantified, and the quality was thus evaluated, the gene-expression patterns were confirmed, as was the fact that cells with the same properties were formed on each occasion. In addition, when a tumorigenesis study was carried out three times, it was confirmed that purified RPE cells do not form tumors.
In future, effective use will be made of the following two tracks, on the basis of a specifically Japanese system: (i) clinical research complying with the Medical Practitioners’ Law; and (ii) clinical studies complying with the Pharmaceutical Affairs Law. It is considered that better treatment methods should be developed, so as to achieve treatment of a global standard.
First Year FY2011
Title Meniscal regeneration in the knee using synovial stem cells
Principal Investigator Ichiro Sekiya
(Director, Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University)
Summary The meniscus is a fibrocartilaginous tissue that contributes to several critical functions within the knee joint, such as load bearing, shock absorption, and joint stability. A meniscal tear is one of the most common injuries of the knee joint. Suture repair of meniscus tears is recommended when feasible to preserve the function of meniscal tissue. However, suture repair is typically only suitable for acute tears that have a longitudinal orientation, although repairs of other more complex acute tears can be selectively performed.
Meniscectomy (partial or total) is the most common arthroscopic procedure performed on the knee joint, but it is correlated with a degenerative change in the articular cartilage and the progression of osteoarthritis. Meniscal injury, degeneration, and dysfunction are distributed widely, increasing from youth to old age, and constitute a problem that must be resolved in Japan with the aging of society.
Mesenchymal stem cells (MSCs) are attractive cell source for cartilage and meniscus regeneration. Our in vitro and in vivo chondrogenic assay demonstrated that synovial MSCs had a high chondrogenic ability. Human synovial MSCs expanded well in human serum. In our several animal studies, transplantation of synovial MSCs promoted cartilage and meniscus regeneration. We already started clinical trial for cartilage regeneration, and the safety and efficacy of this treatment was confirmed. In this project, we are going to study other clinical trial for meniscal regeneration with synovial MSCs.
First Year FY2011
Title Clinical application of corneal endothelial regenerative medicine by means of cultured human corneal endothelial cell transplantation
Principal Investigator Shigeru Kinoshita
(Professor, Graduate School of Medical Science, Kyoto Prefectural University of Medicine)
Subsidiary institution Doshisha University
Summary Healthy corneal endothelial cells are necessary for the maintenance of corneal transparency. However, it is known that human corneal endothelial cells do not proliferate in vivo, and corneal endothelial dysfunction due to disease or injury therefore results in corneal turbidity and a marked deterioration in visual acuity. At the present time, at least 60% of corneal transplantations are performed for the treatment of corneal endothelial dysfunction. However, when such dysfunction is treated with corneal transplantation the prognosis is poor, and there is therefore a constant demand for the development of new and improved treatment methods.
On the basis of the principle that “Corneal endothelial dysfunction develops due to depletion of stem cells in the corneal endothelium tissue, and development of a method for transplanting corneal endothelial cells with a high content of tissue stem cells cultured externally is therefore essential”, by 2011 the present researchers had actively embarked on the research and development of new treatment methods for corneal endothelial dysfunction. In this research, it was discovered that Rho-kinase-inhibitors promote the proliferation of corneal endothelial cells and substrate adhesiveness in primates, and success was achieved with a bulk culture of human corneal endothelial cells with respect to the maintenance of the undifferentiated state, which had previously been difficult. In addition, making use of the effects of Rho-kinase-inhibitors on corneal endothelial cells, as well as giving consideration to new corneal transplantation methods involving the intraocular injection of substrate-free cultured corneal endothelial cells, the usefulness of these cells was confirmed in cell transplantation studies with a cynomolgus monkey corneal endothelial dysfunction model, in which, as in humans, corneal endothelial cells do not proliferate in vivo.
In this project, the first step will be to optimize a novel human corneal endothelial culture medium containing Rho-kinase -inhibitors, and to establish bulk culture methods for human corneal endothelial cells with a high content of stem cells maintained in the undifferentiated state. By means of applied research using corneal endothelial cells from different donors, a cultured human corneal endothelial cell lot applicable to reproducible transplantation to humans will be prepared, the manufacturing and quality-control processes will be optimized, and special analysis and safety studies will be carried out. In addition, in multiple efficacy validation studies using a primate corneal endothelial dysfunction model, the efficacy of human cultured corneal endothelial cell transplantation will be verified, the transplantation method will be optimized, and the safety of cultured corneal endothelial transplantation will be verified. After receiving the verification results, a submission will be made for “Policies for clinical research using human stem cells”, and clinical research on corneal endothelial dysfunction is expected to be initiated at Kyoto Prefectural University of Medicine during 2013. It is hoped that this research will lead to major progress in realizing low-invasiveness and high-function corneal endothelial cell transplantation methods, and that in the future, by participation in multi-site clinical research, and business activities, in Asia, Europe, and the USA, it will also lead to the establishment of corneal endothelial regenerative medicine in Japan, thus representing the global standard.
First Year FY2011
Title Development of a less invasive liver regeneration therapy using cultured human bone marrow derived cells
Principal Investigator Isao Sakaida
(Dean and Professor, Graduate School of Medicine, Yamaguchi University)
Subsidiary institution Foundation for Biomedical Research and Innovation
Summary The objective of this study is to develop a less invasive liver regeneration therapy using autologous bone marrow cells. We have previously been proven to be effective in “autologous bone marrow cell infusion (ABMi) therapy”. To cure more advanced liver cirrhosis patients, we will obtain small amount of autologous bone marrow fluid collected under local anesthesia, will be cultured externally, a less invasive liver regeneration therapy using cultured human bone marrow derived cells via a peripheral vein.
For the above reasons, the safety and efficacy of the infusion of cultured bone marrow mesenchymal stem cells (MSCs), will be evaluated, by means including large-mammal studies, and the proof of concept will be established (this cell fraction has previously been clearly shown to be effective in improving liver functions in fundamental research with mice).
In parallel with the above activities, progress will be made toward establishment of Yamaguchi University’s Cell-Processing Center, and, after regulatory approval of the application “Policies for clinical research using human stem cells”, clinical research will start for patients with advanced liver cirrhosis, which is an off-label indication for current ABMi therapy.

Field "B"
Projects targeting clinical study in the medium to long term

First Year FY2012
Title Development of and clinical studies on platelet preparations based on induced pluripotent stem (iPS) cell techniques
Principal Investigator Koji Eto
(Professor, Center for iPS Cell Research and Application, Kyoto University)
Subsidiary institution Keio University, Japanese Red Cross Kinki Block Blood Center
Summary Platelets are the principal component of blood transfusions. In spite of the importance of their hemostatic function in patients, their stable supply is difficult, because they require room-temperature storage with very short-shelf life, i.e, only 4 days in Japan (5 days in the US). In particular, with many chronic thrombocytopenia patients, who require repeated blood transfusion, there is a need for transfusion of platelet concentrate with the same blood type, in terms of human platelet antigens (HPA) and human leukocyte antigens (HLA), as the patient. Therefore, in the case of a rare blood type, a sufficient number of donors cannot be ensured, making stable supply even more difficult.
The aim of this research is to develop technology for bulk supply of platelets from donor-derived iPS cells with specific blood types, and then to verify safety by clinical research. An additional aim in the future is to establish a bulk stock-on-demand supply system for HLA/HPA-compatible platelets in accordance with the Pharmaceutical Affairs Law. Platelet preparations derived from iPS cells have an advantage in the safety of transplant therapy using iPS cells, because platelets, which are functional cells that lack nuclei and therefore do not proliferate, can be irradiated by ionizing radiation before transfusion, in order to kill contaminating nucleated cells.
Our previous research has successfully derived immortalized megakaryocytes, which are the source for platelet production, from hematopoietic precursor cells, into which iPS cells are induced to differentiate. It was shown that these immortalized megakaryocytes can proliferate even after cryopreserved storage, and, when these megakaryocytes mature through gene-manipulation, they can produce platelets with hemostatic function.
For administration to humans, bulk production of platelets of a consistent quality is required. In future, megakaryocytes with high levels of stability and function will be selected from among established megakaryocyte strains, and a master cell bank of megakaryocytes will be established. We will then develop technologies for large-scale culture, platelet separation/collection, and platelet storage medium that are compliant with good manufacturing practice. After initial clinical research on autologous transplantation, we will establish routine clinical application of platelet preparations derived from iPS cells.
First Year FY2011
Title Development of corneal regenerative treatment methods using iPS cells
Principal Investigator Koji Nishida
(Professor, Graduate School of Medicine, Osaka University)
Subsidiary institution Keio University, Tokyo Women's Medical University
1. Corneal epithelial regeneration
The aims are to treat corneal epithelial stem cell deficiency, which is a condition of complete loss of corneal epithelial stem cells and marked decrease in corneal transparency, due to disease or injury, and to prepare a transplantable cultured corneal epithelial cell sheet from iPS cells. Success has previously been achieved with deriving stratified epithelial stem cells and precursor cells, the origin of corneal epithelial cells, from human iPS cells. These cells expressed K14 and p63, which are markers for stratified epithelial stem cells. In addition, by inducing differentiation of these stratified epithelial stem cells and precursor cells, a cultured stratified epithelial cell sheet was prepared. It was confirmed that the membrane-associated mucins, MUC-1, -4 and -16, which are required for corneal epithelial function, and are expressed specifically, are expressed by the superficial layer of this human-iPS-cell-derived cultured stratified epithelial cell sheet in a similar manner to expression by normal corneal epithelial cells.
In order to verify the function of this human- iPS-cell-derived cultured stratified epithelial cell sheet, a transplantation study was carried out using a rabbit corneal epithelial stem cell deficiency model. The outcome was that collection and transplantation were feasible with the human-iPS-cell- derived cultured stratified epithelial cell sheet. The results of fluorescein-staining on day 8 after transplantation were that, whereas the entire cornea was fluorescein-stained in non- transplanted eyes, indicating absence of the barrier function, little staining was found in transplanted eyes, indicating presence of barrier function. In addition, histochemical analysis showed adherence of the transplanted human-iPS-cell-derived cultured stratified epithelial cell sheet to an extensive area of ocular surface. At the present time, the number of animal experiments has been increased, and the efficacy of human-iPS- cell-derived cultured stratified epithelial cell sheet transplantation is being verified.
2. Corneal endothelial regeneration
With the objective of treating bullous keratopathy, which involves irreversible corneal endothelial injury and decrease in corneal transparency, the aim is to prepare a transplantable, cultured, stratified endothelial cell sheet from iPS cells.
Success was achieved in inducing differentiation of neural crest cells, which are the origin of the corneal endothelium, from human iPS cells. Success was also achieved in inducing differentiation of the iPS-cell-derived neural crest cells, with induction of differentiation to corneal endothelium-like cells. With respect to the human-iPS-cell-derived corneal endothelium- like cells, when expression of collagen type VIII, Na+/K+ ATPase, etc., as selective markers reflecting corneal endothelial cell function, was investigated, it was found that human-iPS-cell- derived corneal endothelium-like cells express all the corneal endothelial markers, and that the expression level is the same as that of cultured normal human corneal endothelial cells. Next, in order to quantify the pump function, which is the principal function of the corneal endothelium, evaluation was carried out using an Ussing chamber system, and it was found that human- iPS-cell-derived corneal endothelium-like cells have approximately the same level of pump function as cultured normal human corneal endothelial cells. Evaluation of the properties and functions on the culture dish has previously been of central importance, but the future plan for evaluation of efficacy, that is, in vivo corneal endothelial function, is to carry out transplantation studies using a monkey bullous keratopathy model.
First Year FY2011
Title Establishment of regenerative therapies for severe heart failure by transplantation of iPS cells-derived cardiomyocytes
Principal Investigator Keiichi Fukuda
(Professor, School of Medicine, Keio University)
Summary Although definite progress is being made with treatment methods for heart failure, the prognosis for severe heart failure patients is still as bad as that for cancer patients, and the principal radical treatment method, heart transplantation, has the major drawback of paucity of donors, so only approximately 4000 transplants are carried out around the world every year. In order to improve the prognosis for severe chronic heart failure patients, there is a need for cell therapies using regenerative cardiomyocytes to be brought into clinical use quickly.
Fundamental research on treatment methods for heart disease using regenerative cardiomyocytes have been carried out at Keio University School of Medicine’s Dept. of Cardiology for the past 10 years. Attention is currently being given to iPS cells as cell therapy resources, capable of providing cardiomyocytes sufficient to improve prognoses for severe heart failure, and we have carried out various studies to ensure the availability of optimal cells for transplantation. Firstly, it has been reported that Noggin, Wnt, etc., are effective for inducing differentiation from embryonic stem and iPS cells to cardiomyocytes. Secondly, it has been clarified that granulocyte colony-stimulating factor (G-CSF) and its receptors are strongly expressed in the fetal heart, and are therefore autocrine growth factors that amplify myocardial cell division, and it has been reported that external administration of G-CSF can markedly increase the numbers of cardiomyocytes differentiated from iPS cells. In addition, in order to avoid risks of tumorigenesis due to mixing with residual undifferentiated stem cells, a method for purification of cardiomyocytes, using mitochondrial fluorescent dye, and based on the metabolic properties of cardiomyocytes, has been developed, and it has been confirmed that transplanted purified cardiomyocytes do not undergo tumorigenesis in immunodeficient mice. Furthermore, a technique has been established for setting up an iPS cell culture from a small quantity of peripheral blood, in less than 1 month, using active T-cells and Sendai virus, without damage to the genome.
In this project, on the basis of data from previous fundamental research, the safety and efficacy of regenerative myocardiocyte transplantation are to be evaluated by transplantation of human-iPS-cell-derived cardiomyocytes into large mammals, primarily pigs, as translational research in progress toward clinical application. With several strains of iPS cell, differentiation to cardiomyocytes will be induced, and bulk culture will be carried out, followed by purification, and then transplantation into healthy Micromini pigs. In addition, by histologically confirming the engraftment of human iPS cells-derived cardiomyocytes, long-term survival, with myocardial structure, is to be confirmed, and tumorigenesis is to be monitored. As the treatment model, human iPS cells-derived cardiomyocytes will be transplanted into myocardial infarction model Clawn miniature pigs, and cardiac function will be evaluated by echography, computed tomography, and magnetic resonance imaging. Furthermore, it will be confirmed whether or not long-term problems with engraftment and/or tumor formation occur even with increases in cell numbers. Whether or not the degree of purity is sufficient will be evaluated, as will the frequency and degree of mixing with undifferentiated stem cells, and, on the basis of feedback as to whether or not the process of myocardial differentiation induction in the culture system is appropriate, protocols relating to the culture and transplantation of human iPS cells-derived cardiomyocytes will be established, as a step toward clinical application.
First Year FY2011
Title Clinical research on human embryonic stem (ES) cell formulations for treatment of congenital metabolic disorders giving rise to severe hyperammonemia
Principal Investigator Akihiro Umezawa
(Deputy Director, Research Institute, National Center for Child Health and Development)
Subsidiary institution Keio University, University of Tokyo, DNA Chip Research Inc.
Summary This research is concerned with development of human ES cells (hESCs)-based products for treatment of pediatric congenital metabolic disorders, and evaluation of their safety and efficacy. In concrete terms, among patients with congenital metabolic disorders who develop hyperammonemia, our transplantation therapy using hESCs-based product is used as a bridging treatment for patients with whom immediate living-donor liver transplantation is rendered difficult by low body weight, absence of donors, etc. The objectives of this program are to evaluate safety, and to reach the stage of clinical research, with the ultimate aims of preventing hyperammonemia-related brain damage, and managing the patient’s general condition, until radical living-donor liver transplantation becomes feasible. Among patients with congenital metabolic disorders who develop severe hyperammonemia, this research will be carried out with patients with whom living-donor liver transplantation is difficult. The hESCs-based product stored in the lyophilized state will be thawed beforehand, and cell transplantation will be carried out by infusion of the cells via the umbilical or portal vein, in order to improve liver function.
The primary object is to analyze for differential propensity of hESC lines (SEES series), and to develop safty and stability of liver differentiation using hESCs. The secondary is to establish a culture system working functionaly hESCs-based products, with the aim of carrying out clinical studies of hESCs-based products in accordance with guidelines and instructions scheduled for release by the Japanese Ministry of Health, Labour and Welfare. The results of this research present a model not only of congenital metabolic disorder patients with associated severe hyperammonemia, but also for progression toward clinical application of hESCs-based products.

Field "C"
Supporting other projects in views of safety and efficacy of stem cells and their products

First Year FY2011
Title Support for research and development with the aim of early-stage realization and overseas expansion of regenerative medicine
Principal Investigator Akifumi Matsuyama
(Director, Research on Disease Bioresources, Platform of therapeutics for rare disease, National Institute of Biomedical Innovation)
Summary In this research area, on the basis of experience with realization of regenerative medicine, and the results of regulatory studies, with the Foundation for Biomedical Research and Innovation, consistent support will be given, from an early stage of research and development, for rapid realization and overseas expansion of selected research projects. In order to achieve these goals, the following three sub-projects will be coordinated, on the basis of collaboration with the Innovative Therapies Response Section of the National Institute of Health Sciences: (i) support for research theme management; (ii) support for clinical expansion; and (iii) support for social acceptance.
1. Research Theme Management Support Sub-Project
For project management of each selected theme, supports are given for management of progress in provision of the portfolio information to PD, PO, regulatory organizations and operating committees. In addition, on the basis of information centralized and standardized in the Clinical Expansion Support Sub-Project, research results, etc., needed for surveys and research relating to reassessment of the various regulations are provided. With the aim of rapid clinical application of selected themes, the preliminary dispute points relating to the preliminary consultation before the regulatory strategy consultation will be organized, the questions and answers for the face-to-face consultation will be collated, and measures will be taken for provision of explanations and elucidations to the personnel responsible for each research theme.
2. Clinical Expansion Support Sub-Project
Support will be given to decisions about, and submission of, related documents, including protocols for human stem cell clinical studies and other clinical research; contributions will be made to collation of research-related data, etc., and their preparation as electronic media, and management; researchers and technologists will be introduced from various institutions; and training in and technology transfer for cell formulation production will be carried out. In addition, a portfolio management system will be established and operated for realization of regenerative medicine. Next, as progress toward clinical expansion at each institution, together with preclinical and nonclinical research-related data, know-how, etc., being collated, prepared as electronic media, and managed, the rules for allocation of benefits will be defined if use is approved, and benefits are demonstrated, and work will be made toward promotion of sharing and standardization of data, with provision of incentives, with the aim of achieving competitive and synergistic effects with other research themes.
3. Social Acceptance Support Sub-Project
Efforts will be made with intra-project information exchange and sharing by workshops, and information release by presentation at symposia, and other venues for dialogues with the Japanese population about science and technology, so as to contribute to progress by the company as a whole in cooperation with self-helped patient groups (outreach activities).
The above three sub-projects will be combined in a coordinated manner, and support will be given for research and development toward early-stage realization and overseas expansion of regenerative medicine.

Field "D"
Ethics research and consultation related to realization of regenerative medicine

First Year FY2011
Title Research on the ethical, legal and social implications related to regenerative medicine
Principal Investigator Kaori Muto
(Professor, Department of Public Policy, The Institute of Medical Science, The University of Tokyo)
Subsidiary institution Showa University
Summary In order to make regenerative medicine more concrete, it is essential to promote research development with a definite focus on clinical applications, and to establish a framework for clinical research at an early stage. We need to provide researchers at each institution with ethical support from the very beginning of their basic research and to have the Institutional Review Boards (IRBs) examine it thoroughly to make sure that they implement clinical research in an appropriate way. On the other hand, it is the case that we have considerable differences among research institutions in terms of the quality of the Japanese systems for ethical support and review; this is quite far from a standardized system. Moreover, it has been said that we might have ethical issues unique to the field of regenerative medicine, but we are not sure how ethical support and review specific to this field should be. This program then offers concrete ethical support to those researchers, research facilities and IRBs. Furthermore, we organize interdisciplinary research groups to address the ethical, legal and social implications (ELSI) related to regenerative medicine in a comprehensive manner, with a view to establishing a framework for ethical support and review of regenerative medicine.
In particular we carry out our research and support activities from the following three viewpoints:
1. Support of researchers
We set up a benchside consultation to give advice to individual researchers themselves and their specific research protocols.
2. Support of research institutions
We develop and offer a flow-sheet showing how to conduct ethical reviews, common forms of informed consent, and training programs for IRBs to ensure that each research institution implements ethical reviews, taking the characteristics of regenerative medicine into account.
3. ELSI research
We take a problem-solving approach toward the ELSI of regenerative medicine so that the promotion of research on regenerative medicine can keep in harmony with social values. This approach requires interdisciplinary research groups, who can conduct not only social surveys but also theoretical studies. Specifically, this program engages in both theoretical and empirical studies on particular issues such as translational research, stem cell banks, stem cell tourism, and human-animal hybrid cells/chimeric cells. We conduct a series of surveys of researchers’ and public perception about research on regenerative medicine after examining regulations of other countries and trends of bioethical literature. It is our ultimate goal to make a settlement proposal on each ELSI of regenerative medicine with reference to current situations in Japan.
Research Center Network for Realization of Regenerative Medicine
Japan Agency for Medical Research and Development(AMED)
Regenerative Medicine Division,
Department of Strategy Promotion

1-7-1 Otemachi, Chiyoda-ku,Tokyo, 100-0004 Japan
Phone: +81-3-6870-2220
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