Future Pharmaceutical Sciences and Recent Advancement of Medical Sciences

1. Future Pharmaceutical Sciences and Recent Advancement of Medical Sciences Kunio KAWAMURA, Ph.D. Otsuka Pharmaceutical Co. Ltd.

2. Outline of this speech-1 Following two topics will be presented as representatives Co. Application of iPS: iPS cells are engineered by introducing specific genes into cells derived from the skin, blood and other body tissues. They have the potential capacity to develop into cells of various parts of the body. The first clinical study has just started to treat age-related macular degeneration, an intractable disease of the eye. iPS cells turn into pigment epithelial cells, and thereafter, are cultivated to multiple applicable sheets for transplants to many patients. The cultivated cell sheets will be a kind of medical device. The application is now expanding to various medical sciences.

3. Outline of this speech-2 (2 ) Clinical trials using therapeutic porcine cell implants have already been at the final stage. Microspheres containing live pig’s islet cells are implanted into a patient's abdomen. Once implanted, the encapsulated islet cells work by self-regulating and efficiently secreting insulin and glucagon in response to the patient's changing glucose levels. The capsules containing islet cells are protected from the body's immune response by the semi-permeable membrane, and also permit the bidirectional diffusion of molecules essential for cell metabolism and the outward diffusion of waste products. This technology is now being extended to treat other diseases. Those encapsulated cells will be categorized as combination products

4. Human Organs/Cells Transplantation 1．Shortage of Donors 2．Utilization of iPS Cells 1) Use of Human Cells (ex. Conversion from Human skin cells) 2) Generation of Human Organ in Animal by Animal-Human Chimeric Embryo Technology (ex. Human Blood in sheep. Human Heart and/or , spleen in Pig) 3. Make use of Animal Organ by an New Invention to Eliminate Rejection Reaction． Clinical trials are now progressing for 2-1) and 3. These have need for new concept of pharmaceutical sciences.

5. Transplantation of Organ in Human Current situation

6. Human-Human Heart Transplantation in Japan Waiting Transplanted

7. Organ, Tissue and Cell Transplantation Generation of Human Organ, Tissue and/or Cells from iPS Cells Generation of Human Organ, Tissue and/or Cells in Animal by Elimination Rejection 3. Making Use of Animal Tissue or Cell, as it is, by Elimination Rejection

8. Mechanisms of Rejection Reaction Lymphocytes/Immune cells attack the Transplanted Organ Lymphocytes/ Immune Cells Transplanted Organ

9. In order to Reduce Rejection reactions There are two methods. One is to use the same kind of biological products. ex. Human – Human transplantation. The second is to make change the differences to harmonize, by make use of genetic technology. ex. using iPS cells. 3) The third is to protect cells from the rejection reactions by artificial barriers. ex. Protecting cells by blocking higher molecular barrier.

10. Examples of New Type of Pharmaceuticals and Medical devices ・Generation Retina sheet for multi-patients, (under clinical trial) ・Generation of Blood/Blood cells in animals formulti- patients, ・Encapsulated Insulin Secreting Pig cells ( under clinical trial) Pharmaceutical science should cooperate and contribute the completion of these technology, and have to care how to deliver, storage and use.

11. ES Cell and iPS Cells Embryonic stem cells are able to develop into any type of cell. Embryonic stem cells (ES cells) are pluripotent stem cellsderived from the inner cell mass of a blastocyst,an early-stage embryo. Human embryosreach the blastocyststage 4–5 days post fertilization,at which time they consist of 50–150 cells. Isolating the embryoblastoor inner cell mass(ICM) results in destruction of the fertilized human embryo, which raises ethical issues. Induced pluripotent stem cells, abbreviated as iPS cells are a type of pluripotent stem cellartificially derived from a non-pluripotent cell – typically an adult somatic cell– by inducing a "forced" expression of specific genes.Induced pluripotent stem cells are similar to natural pluripotent stem cells, such as embryonic stem (ES) cells,in many aspects. Induced pluripotent cells have been made from adult stomach, liver, skin cells and blood cells.

12. Four kinds of genes Skin Cells Reset CELLS How to manufacture iPS Cells Cells Muscle cells Skin Cells Nervous Cells White Blood Cells Red Blood Cells

13. Application of iPS Cell Technology to Medical science The first case of iPS Cell thechnology to medical sciences. “ Age-Related Macular Degeneration：iPS Cells-Derived Retinal Pigment Epithelium Cell”

14. Medical Treatment of Age-Related Macular Degeneration for Eye Patients of Age-Related Macular Degeneration for Eye Cells 10 months Skin Cells Genes into Cell iPS Cells Macula Cell sheet Trans Plantation

15. iPSCells RtinalPigment Epithelium Cell Cultured cells are Transplanted to Retina Age-Related Macular Degeneration ーiPS Cells-Derived Retinal Pigment Epithelium Cell Sheey（シートを将来市販する：医療機器） Cultured to Cell sheet Retinal Pigment Epithelium Cell Eye lens

16. The second Case: XenotransplantationHuman-animal Transplantation

17. Embryo Animal Embryo Animal-Human Chimeric Embryo Human Cells

18. Use of Animal Organ –Xeno-trans-plantation- 1．How to Overcome Rejection/ Immune 2．Ethics of Life

19. Human iPS cells Birth of animal with human pancreas Human Organ (Pancreas) cultivated in Pig Injection to animal womb and incubate Genetically manipulated Embryo Fertilized egg

20. Method 3 Making Use of Animal Tissue or Cell, as it is, by Elimination Rejection

21. Nutrition, Oxygen Insulin Anti-Body Pig Islet Cells Semi-permeable Membrane

22. Cell Encapsulation

23. Animal Organ from Pig cells to be TransplantedGet animation: Processing pig cells for transplants

24. Capsules Containing Cells

25. Islets isolated from neonatal porcine pancreas in alginate-polyornithine

26. Capsules for sale ( Before Use)

27. Label of Clinical Use Product

28. Diabetes Treatment Utilizing Implanted Encapsulated, Insulin-Producing Cells Would Replace Existing Type 1 Diabetic Drugs

29. 1. iPS cell technology is usefull and promising in future,2. Living cell encapsulation technology will also have various future application.

30. Thank you for your attention Kunio KAWAMURA