Future Pharmaceutical Sciences and Recent Advancement of Medical Sciences

Kunio KAWAMURA, Ph.D. Otsuka Pharmaceutical Co. Ltd.

Outline of this speech-1 Following two topics will be presented as representatives

Co.

(1) 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.

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

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.

Transplantation of Organ in Human

Current situation

Human-Human Heart Transplantation in Japan

Waiting

Transplanted

Organ, Tissue and Cell Transplantation

1. Generation of Human Organ, Tissue and/or Cells from iPS Cells

2. 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

Mechanisms of Rejection Reaction

Lymphocytes/Immune cells attack the Transplanted Organ

Transplanted Organ

Lymphocytes/Immune Cells

In order to Reduce Rejection reactions There are two methods.1) One is to use the same kind of biological

products. ex. Human – Human transplantation. 2) 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.

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.

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 cells derived from the inner cell mass of a blastocyst, an early-stage embryo . Human embryos reach the blastocyst stage 4–5 days post fertilization, at which time they consist of 50–150 cells. Isolating the embryoblasto or 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 cell artificially 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.

How to manufacture iPS Cells

CELLS

Four kinds of genes

Reset

Muscle cells

Nervous Cells

Skin Cells

Cells

Skin Cells

Red Blood CellsWhite Blood Cells

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”

Medical Treatment of Age-Related Macular Degeneration for Eye

Patients of Age-Related Macular Degeneration for Eye

Skin Cells

iPS Cells

10 months Cells

Genes into Cell

Macula Cell sheet

Trans Plantation

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）

iPS Cells

Cultured to Cell sheet

Cultured cells are Transplanted to Retina

Rtinal Pigment Epithelium Cell

Eye lens

Retinal Pigment Epithelium Cell

The second Case: Xenotransplantation Human-animal Transplantation

Animal-Human Chimeric Embryo

Human Cells

Animal EmbryoEmbryo

Use of Animal Organ –Xeno-trans-plantation-

1 ． How to Overcome Rejection/ 　　　 Immune 2 ． Ethics of Life

Human Organ (Pancreas) cultivated in Pig

Fertilized egg

Human iPS cells

Genetically manipulated Embryo

Injection to animal womband incubate

Birth of animal with human pancreas

Method 3

Making Use of Animal Tissue or Cell, as it is, by Elimination Rejection

Nutrition, Oxygen

　 Anti-Body

Semi-permeableMembrane

Pig Islet Cells

Insulin

Cell Encapsulation

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

Capsules Containing Cells

Islets isolated from neonatal porcine pancreas in alginate-polyornithine

Capsules for sale ( Before Use)

Label of Clinical Use Product

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

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

Thank you for your attention

Kunio KAWAMURA