The Road to Total Disease Control- Regenerative medicine as an ultimate ofprecision medicine
The principles, present status and scope

Masanori Fukushima, MD, Ph.D.
Director and Chairman, TRI
Professor Emeritus, Kyoto University

Founded in 2002 by the
Ministry of Education, Culture,
Sports, Science and Technology(MEXT）and Kobe City, as thefirst academic data center forclinical researches in Japan.

What is learning, for what and how?

學不可以已。學至於行之而止矣。

（荀子）
大上有立徳、其次有立功、其次有立言。
（左伝）

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Today’s Topics
1. Introduction – we are living in unprecedented
science revolutionary age
2. What kinds of services and supports
TRI provide, and our accomplishments

3. Explore the life/living organisms as it is
4. Principles of regenerative medicine

5. Examples of regenerative medicine－Results from clinical trials
6. What should be done next

2019/8/6

Wu Ta-You Science Camp

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Ongoing Science & Technology Revolution
in Medical / Healthcare field

1. Genome ・ Immunology
2. Stem cell ・ Exosome

3. Robotics ・ BMI/BCI
4. Nanotechnology ・ Sensing

5. IoT ・ AI
Human exceed human
Machine exceed human

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Singularity

3

What is SCIENCE ・・・Definition

To observe* the interrelation of thingsand cause/effect in the universe as it is,

describe and explain exactly what you
have recognized*includes to formulate, execute, and observe the experiment2016.4.12 M. Fukushima

Scientists explore the world as it is,rather than as they would like it to be.
『Nature』 449. 25 Oct, 2007
Editorials “Watson’s folly”

唯仏与仏 乃能究尽 諸法実相 （Lotus sutra)
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What mankind are doing

Explain the nature as you have recognizedPredict and intervene nature to
make it as one would like it to be⇒ Technology

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Science and Technology

Science and technology
without philosophy

are madness

2

E = mcRight and wrong differs among individual person.
Future of humanity is in your hands.
What do you see beyond AI evolution?
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What is ETHICS・・・Definition

Consensus and/or request of the society
in which the person belongs to.

The appropriate behavior -words and actions,in which the person lives at that time.
2016.4.7 M. Fukushima

Ethics: a set of moral principles
in human conduct(Ref: Oxford Dictionary）

The School of Athens by Raphaelo illustration cited from Wikipedia:
https://en.wikipedia.org/wiki/The_School_of_Athens
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What is CLINICAL SCIENCE・・・Definition

Essential knowledge to solve various
problems affecting human health,and the methodology to generate them
→ To clarify necessary and adequate

measures and roadmaps to achieve
desirable goal, and to implement themstrategically"Medicine is a science of
uncertainty and art of probability”- Sir William Osler

Scienceby the human, for the human, of the human
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Science vs Business

Scientists explore the world as it is,
technology/business act to the world
as they would like it to be ・・・but notnecessarily true

Technology/BusinessWisdom (Law, Ethics)
智慧 (倫理)Drive R&D

Science

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9What is Medical R&D

Required Mindsets
Research & Development (R&D) of drug/medical
devices/medical procedure should not be driven
by researcher’s own interest, but is a productdevelopment operation and legal processassembling science & technology based on law,aiming for the goal of attaining approval fromthe authority.

Registration Clinical Trials is the solution
Under the Pharmaceuticals and Medical Devices Act
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10What is REGULATORY SCIENCE

Regulatory science requires thestate-of-the-art scientific rigor at
the time based on humanity,

which should be managed andguaranteed by the law.
2011.1.8 M. Fukushima

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11The collision of logic/ethics between Academia
and Commercial companies

Invested money should be collected.
Moreover,should make a profit.

However,
medical R&Ds are
NOT for making
money !

Return on Investment (ROI)
Academic
logic/ethics

LIVING

Corporate
logic/ethics
Capital gain/profit

Disease control/cure

LIFE
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Within medical R&D competition---Is science a slavery of business?

＜我見諸衆生没在於苦海＞

ScienceBusiness
Liberal ocean on economic market⇒ vicious cycle
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Health care vs. Economics

For total disease control, we need
new theory or principles of economics
Issue of re-distribution of wealth
Poverty is the major cause of disease

The question is can we achieve our goal
through existing social economic system,
per se capitalism for market?
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Ongoing Science & Technology Revolution
in Medical / Healthcare field

1. Genome ・ Immunology
2. Stem cell ・ Exosome

3. Robotics ・ BMI/BCI
4. Nanotechnology ・ Sensing

Janus image cited from Wikipedia
https://en.wikipedia.org/wiki/Janus

5. IoT ・ AI
Human exceed human
Machine exceed human

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Singularity

15

Types of innovation【J. Schumpeter】

Tailored-type Service

Material → Manufacture → Production → Product → Distribution

Philosophy / Science / Technology

・Individual base・Population base

Genome, exosome innovation
Stem cell, immuno-cellular Innovation
Digital Health Innovation

AI assisted science & health care system(Learning health care system)
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Feature of Disruptive Innovation
Disruptive innovation refers to economic activities such as products
and services which have the impact of destroying existing market
value and converting the market into a whole new value system（Clayton M. Christensen, “The Innovator's Dilemma”)

Double S-curve 【R. Foster】• Non-contiguous(change of personnel)

Drug therapy

Accomplishment• Types• Investments• Entrepreneurs
Cellular therapy

Labour and fund invested
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Today’s Topics
1. Introduction – we are living in unprecedented
science revolutionary age
2. What kinds of services and supports
TRI provide, and our accomplishments

3. Explore the life/living organisms as it is
4. Principles of regenerative medicine

5. Examples of regenerative medicine－Results from clinical trials
6. What should be done next

2019/8/6

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Grand design -Toward Total Disease Control
Central dogma - Practice of Science
We can accelerate this cycle dynamicallythrough global data sharing

Disease-specific Registry- complete enrollment
TR

Clinical Trial

Data
CenterNew
Drug/Devise
Reverse TR

Outcomes
Research

Big Data
AI assisted

Real World Individual Participant Data

Population-based Life courseEnterprise
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Cure andOvercome All
DiseasesStandardization& Harmonization
REQUIRED !

19

TRI’s organization structure to achieve its goal
GOAL

➢ Healthy Centenarian➢ 0 Bed-ridden

Digital Health Innovation

Division of Health Data Science
projects

Guidelines

Registry
Sales&
MarketingOrdersBusiness
Development Group

Science
Statistics

R&D
Pipeline

Division of Medical Innovation

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Approvals

projects

Wu Ta-You Science CampIT System
Automation/ AI
utilization

Regenerative therapeutics:① Vocal cord (titanium bridge)② Cerebral nerve/ bone marrow(CD105 cell)③ Eardrum (bFGF/gelatin sponge)④ Blood vessel (CD34 cell)⑤ Bone (CD34/atelocollagen)⑥ Cornea (Mucous membrane cell sheet )⑦ Cartilage (Cartilage cell/collagen)・・・
20

TRI Operation- Support Clinical Trials & Medical R&D➢ The one and only Data Center for academia
Provide comprehensive clinical trial management services for studies ofall phases from research planning to data analysis.
R&D Strategy

Clinical trial

1. R&D policy・Market analysis・Competitive Research
・R&D scheme・R&D truck

2. Patent strategy
・Patent consultation
・Patent research support

2. Clinical trial management – launchand operation of trials
3. Data Management
4. Statistical analysis

3. Non-clinical・Efficacy ・Safety ・Test material production

4. Collaborations with joint development(Liaison）
5. ARO framework construction support

2019/8/6

1. First-in-man study protocol
development and regulatory relations

5. System development (ex. EDC)
6. Global clinical trial support – planning,launch, and operation
7.

Monitoring and Audit

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【リンゴ位置変える】TRI Achievement- Pipeline, Approval and Market
TRI aims for disease control and healthy life extension.
From our past activities, some major diseases that cause long-term care, areexpected to be overcome.
In the future, we will strongly promote digital health innovation and contributeto the extension of the healthy life span.

EardrumBloodvesselCartilage

Approval/NDA
Clinical trial/To be
submitted for NDA

CorneaBone

New R&Ds
Nerve,
Vocal Spinal
cords cord

●TRI Establishment＊●15th anniversary

Feedback to citizens

Ability to communicate is essential to live centenarian society.
Vocal
cords

Eardrum

CorneaRegeneration of eardrum, vocal cords, and cornea make it possible to “hear”, “talk”,
and “see”.

＊Vocal cords: TITANBRIDGE, December 15, 2017, approval (The first approval in SAKIGAKE Designation System!!)＊＊
Nerve,
Spinalcord

We devote ourselves to reduce bed-ridden, care-needed patients.
Blood
vesselCartilage

Bone

Regeneration of nerves, blood vessels, and cartilage will lead to independent living from lower
limb amputation caused by stroke, spinal cord injury, Buerger’s disease, and ASO, and othervarious bed-ridden, care-needed causes.

＊＊Nerve, Spinal cord: Stemirac, December 28, 2018, conditional and time-limited approval
Dementia

2019/8/6

Prostate Coloncancer cancer

Arterial
sclerosis

New therapies are under development for the treatment of dementia, prostate cancer, coloncancer, arterial sclerosis.
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Examples of TRI-supported serves

TRI Advances

https://advances.tri-kobe.org/

https://advances.tri-kobe.org/en/research/8/-a-stem-cell-fix-for-spinal-injury
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Nature Outlook 2016 ／ Outline 2017Vol. 540 No.S49, December 7, 2016

Nature Outlook: Regenerative medicine

Theorywww.nature.com/articles/540S49a
Vol. 544 No.7650_supp_out,April 20, 2017

Corneal repair

Preparing
NDA

https://www.nature.com/collections/pdryjrsvnz/videos
Vol. 546 No.7659_supp, June 22, 2017

Eardrum regeneration: membrane repair
https://www.nature.com/collections/rzfrydkflp/videos
Vol. 548 No.7668_supp, August 24, 2017

Critical limb ischaemia
https://www.nature.com/collections/vmxkcnxvwg/videos
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Approved on
Aug 1. 2019

Registration
trial
ongoing24

Nature Outline 2017 - 2018
Vol. 550 No. S193, October 26, 2017

Non-union bone fracture: a quicker fix
https://www.nature.com/collections/qmpthxknbn/videos

Registration
trial
ongoingVol. 552 No. 7684_supp, December 14, 2017

Spinal-cord injury: spurring regrowth

Approved/
Launched

https://www.nature.com/collections/ctdkppqqnx/videos
Vol. 563 No. S33, November 7, 2018

Ulcerative colitis
https://www.nature.com/collections/qwtdpjcrpg/video

Registration
trial
ongoingVol. 564 No. S73, December 20/27, 2018

Liver Cirrhosis
https://www.nature.com/collections/ycpfrvtnhj/video
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Registration
trial
ongoing25

First round of regenerative medicine
has been completed
Type of regeneration

Approved

Nerve

Dec. 20, 2018

(auto serum-expanded
autologous CD105
mesenchymal stem cells)

Approved

Eardrum

Aug. 1, 2019(bFGF/gelatin sponge)

Under trial

Blood vessel

Target Disease
Spinal cord injury

Bone

Shinichi Kanemaru(Kitano Hospital)

Critical Limb Ischemia

Atsuhiko Kawamoto（TRI）

Refractory bone fracture(CD34/atelocollagen)Preparing
NDA

CorneaUnder trial

Cartilage

Ryosuke Kuroda(Kobe University)

Corneal epithelial stem cell deficiency

Chie Sotozono(Kyoto Prefectural
University of
Medicine)

Cartilage injury

Hiroyuki Ishibashi(Hirosaki University)(Mucouse membrane cellsheet)(Cartilage cell/collagen)2019/8/6

Osamu Honmou(Sapporo Medical
University)

Tympanic membrane(CD34/cell)

Under trialPI

Wu Ta-You Science CampSAKIGAKE
Designation★
February
2016

★
March
2018

★
March
2018

26

Today’s Topics
1. Introduction – we are living in unprecedented
science revolutionary age
2. What kinds of services and supports
TRI provides, and our accomplishments

3. Explore the life/living organisms as it is
4. Principles of regenerative medicine

5. Examples of regenerative medicine－Results from clinical trials
6. What should be done next

2019/8/6

Wu Ta-You Science Camp27

Group blindness evaluation

群盲撫象

・・・ far from as it is!

Image cited form Wikipedia https://en.wikipedia.org/wiki/Blind_men_and_an_elephant
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Scientific procedure: recognition always underrestraint by individual perception

Science is preoccupied with inductive inference
as experimental science
Inductive inference

hypothesis/principles/theory
deduction

explain the nature based on the hypothesis
test hypothesis

To gain insight deeply, in particular,
the understanding of life, AI, humanity, biologicalprinciples derived from the research axiomatic system
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Science based on epistemology:
theory of knowledge

Deduction

演繹 と 帰納
Induction

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Understanding the world/life:
prediction of phenomena

Laplace’s Demon

Stochastic

Deterministic:
Mechanistic

Maxwell’s Demon
Demon illustration cited fromhttps://www.atlasobscura.com/articles/dem
ons-illustrations-dictionnaire-infernal

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Science: level of recognition

Epistemology
Theory of knowledge

Unsolved
QuestionsAxiomatic
System・integrity

phenomenalism

substantialism
essentialism

1. origin, evolution
2. life duration
3. consciousness

・homeostasis
・self-organization・scaffold field・symbiosis
・rhythm resonance,synchronization

・symmetry2016.5.9 M. Fukushima
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Developmental stage-1
Diagnostics and therapeutics
Level of disease control

science（level ofrecognition）

diagnosis

treatment

evaluation

phenomenalism

Symptomatic

Symptom
control

Surrogate
endpoint

Event control

True endpoint

substantialism

Pathophysiological
Genetical

essentialism

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Etiological

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Developmental stage-2
Diagnostics and therapeutics
Level of disease control

science（level ofrecognition）
phenomenalism

Approaches
probabilistic

analyticmechanistic

deterministic

integrative

holistic

substantialism

essentialism

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Today’s Topics
1. Introduction – we are living in unprecedented
science revolutionary age
2. What kinds of services and supports
TRI provide, and our accomplishments

3. Explore the life/living organisms as it is
4. Principles of regenerative medicine

5. Examples of regenerative medicine－Results from clinical trials
6. What should be done next

2019/8/6

Wu Ta-You Science Camp35

Stem cell medical revolution

New paradigm of medicine using theessence of natural healing force
Autologous or allogeneic stem cells derived frombone marrow, adipose tissue etc.

Newer conception of disease
regenerative homeostasis failure

Indicates to majority of intractable diseases

Copernican
revolution

2019/8/6

Paradigm change ofdrug discovery &development
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The Biological Principles oftissue regeneration in the body -1

Stem cell which play major role in tissue
repairing/regeneration are widelydistributed over the body tissues,connective tissues, adipose tissue, bonemarrow, and it was preserved through theprocess of evolution.

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The Biological Principles oftissue regeneration in the body -2

Stem Cell is naturally existing in the
blood, circulating the whole bodyand serving turn-over of the tissue
cells, repairing and regeneration of

the tissues.

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The Biological Principles oftissue regeneration in the body -3
When some tissue are damaged, … signaling
Stem cells catch the signals from the damaged tissue … perception
Stem cells are mobilized to blood flow, … mobilization
Stem cells are homing to the damaged area, … homing
Stem cells perform required conditioning of the damaged area,…conditioning
Triage dying cells and survivable cells, eliminate the former, andprotect/ rescue the latter cells, suppressing inflammation
conversion of M1 to M2, control permeability of the micro-vasculature,
Reconstruct/regenerate micro vascular architecture,supply oxygen and nutrients for survivors, and then regeneration
process begins. … repairing, regeneration
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39The Biological Principles oftissue regeneration in the body -4

When the tissue damage is massive and beyond
natural healing capacity i.e. insufficient numberof stem cells which is mobilized as a naturalprocess, re-infusion of expanded stem cells

derived from autologous bone marrow or fromharvested circulating stem cells help theprocess of tissue regeneration as natural
healing autonomic process.

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Multicellular symbiotic system for maintaining
homeostasis that inherits self-preserving ability

Microbes

InjuryM2↓↑
M1

Cell damage/
Necrosis

Degeneration
Prionoid

Infarct

Clearance(phagocytosis)
Neoplasm
Invasion

Reconstruction(regeneration)

Self-non-selfrecognition

Resetting the innate
immune system

Ref: Nature Outlook: Regenerative Medicine, December 7, 2016
Figure 2. Mechanisms regulating maintenance of normal functioning of multicellular symbiotic systems.
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Physiology and pathology of stem celland its molecular basis
Phenomenon

Damage →Signaling

Necrosis
Apoptosis↓
Mobilization↓
Homing↓Inflammation↓
Conditioning
Clearance(phagocytosis)
・anti inflammatory
・trophic action
・vascularization
・others↓
Differentiation
Regeneration
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Cell EV

Cell

Exosomemitochondria?
miRNA

Cytokine,
others
SDF-1/CXCR4,
S1P/S1PR
HMGB1/RAGE?, etc.

MSC, Muse cell
(SSEA3+)
CD105
CD34

M1→M2, HGF, etc.
NGF
VEGF, etc.

Wu Ta-You Science Camp42Current status on regenerative medicine I

First round of regenerative medicine
clinical development- Disruptive Innovation Phasehas been completed, and entered into
second round
First round: biological principle concerning
tissue regeneration

ー clarification of cell-generation process andestablishment of its utilization
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Today’s Topics
1. Introduction – we are living in unprecedented
science revolutionary age
2. What kinds of services and supports
TRI provide, and our accomplishments

3. Explore the life/living organisms as it is
4. Principles of regenerative medicine

5. Examples of regenerative medicine－Results from clinical trials
6. What should be done next

2019/8/6

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44The Principles of Regenerative Medicine

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The Principles of Regenerative Medicine
Stem cell therapy and tissue engineering therapy

Preface
Theory: An overview of regenerative medicine: its principles andthe scope of the current revolution
1
Stem Cell Therapy

2
3
4

Tissue Engineering

5
6

2019/8/6

Prof. Honmou,
Spporo medical Univ.

Profs. Minatoguchi & Dezawa,
Gifu Univ. & Tohoku Univ.

Dr. Kawamoto,
TRI

Prof. Kuroda,
Kobe Univ.

Prof. Sotozono,
Kyoto pref. Univ.

Dr. Kanemaru,
Kitano Hosp.
Wu Ta-You Science Camp

Nervous system
Myocardium
Vascular
Bone
CorneaEar drum46

Fine architecture of nervous system:neuro-vascularization complex symbiotic system

Ref： Neuron. 2017 Sep 27;96(1):17-42.
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Spinal-cord injury: spurring regrowthVol. 552 No. 7684_supp, December 14, 2017

Spinal-cord injury: spurring regrowth
https://www.nature.com/collections/ctdkppqqnx/videos
Prof. Osamu Honmou
Department of Neural Regenerative Medicine, Research Institute for Frontier Medicine,
Sapporo Medical University School of Medicine, Sapporo, Japan
Publication

Honmou O., et al.
Intravenous administration of auto serum-expanded autologous mesenchymal stem cells instroke.
Brain 2011: 134; 1790–1807.
Honmou O., et al.
Mesenchymal stem cells: therapeutic outlook for stroke.
Trends in Molecular Medicine 2012 May;18(5); 292-7.

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MSC for Stroke

Figure Magnetic resonance imaging images of patients’ brains before and after theadministration of mesenchymal stem cells.

Ref：Honmou et al., Intravenous
administration of auto serum-expanded
autologous mesenchymal stem cells instroke.
Brain 2011: 134; 1790-1807.

Figure Effect of administration of mesenchymal stem cells on the NIH stroke scale(NIHSS) of patients.
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ASIA score transition in spinal cord injury- from Guideline of ICCP in US (issued 2007)
cervical
ASIA AASIA B
ASIA CASIA DASIA E
total
cervical
ASIA AASIA B
ASIA CASIA DASIA E
total
cervical
ASIA AASIA B
ASIA CASIA DASIA E
total

2day
○

2day
○

○

week 4week 8week 16 week 26 week 52
252
221
202
202
188
29
39
43
47
33
13
21
20
27
25
4
13
17
19
294
285
278
293
265
week 4week 8week 16 week 26 week 52
9
8
6
7
5
49
34
28
25
23
28
25
19
20
11
9
25
37
41
44
1
1
3
6
6
96
93
93
99
89
week 4week 8week 16 week 26 week 52
1
22
17
0
40

12
28

8
32

6
32

40

40

38

From w4 (d28) to w52 (1y)ASIA A ⇒ B/C/D
17.2 %

ASIA B ⇒ C/D/E
49.4 %

ASIA C ⇒ D
71.3 %

Ref: Guideline of ICCP（International Campaign for Cures of Spinal Cord Injury Paralysis）
Fawcett JW, Curt A, et al. . Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: spontaneousrecovery after spinal cord injury and statistical power needed for therapeutic clinical trials. Spinal Cord. (2007) 45:190–205. PMID: 17179973
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Stemirac: Approval of autologous MSC forspinal cord injury (issued Nov. 21, 2018)2019/8/6

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Package insert for Stemirac

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Stemirac : Summary basis of approval(issued on Nov. 21, 2018)
http://www.pmda.go.jp/regenerative_medicines/2019/R20190125001/530100000_23000FZX00001_A100_1.pdf

http://www.pmda.go.jp/regenerative_medicines/2019/R20190125001/530100000_23000FZX00001_A100_1.pdf
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MSC Therapy for forthcoming application－Pre-clinical POC• chronic cerebral infarction

Komatsu, K., et al. Therapeutic time window of mesenchymal stem cells derived frombone marrow after cerebral ischemia. Brain Res. 1334, 84–92 (2010).
Namioka, T., Namioka, A., Sasaki, M., Kataoka-Sasaki, Y., Oka, S. et al. Intravenous
infusion of mesenchymal stem cells promotes functional recovery in a rat model ofchronic cerebral infarction. J. Neurosurg. https://doi.org/10.3171/2018.5.JNS18140(2018).

• cerebral hemorrhage

Nakazaki, M., et al. Intravenous infusion of mesenchymal stem cells inhibits intracranial
hemorrhage after recombinant tissue plasminogen activator therapy for transient middle
cerebral artery occlusion in rats. J. Neurosurg. 127, 917–926 (2017).

• chronic spinal cord injury

Morita, T., et al. Intravenous infusion of mesenchymal stem cells promotes functional
recovery in a model of chronic spinal cord injury. Neurosci. 335, 221–231 (2016).

• post-resuscitation
encephalopathy

Zheng, W., et al. Therapeutic benefits of human mesenchymal stem cells derived frombone marrow after global cerebral ischemia. Brain Res. 1310, 8–16 (2009).

• Parkinson’s disease

Inden, M., et al. Therapeutic effects of human mesenchymal and hematopoietic stem
cells on rotenone-treated Parkinsonian mice. J. Neurosci. Res. 91, 62–72 (2013).

• prion disease

Song, C. H., et al. The effect of transplantation of bone marrow-derived mesenchymal
stem cells on mice infected with prion. J. Virol. 83, 5918–5927 (2009).

• hypoxic ischemic
encephalopathy in thedeveloping brain

Sakai, T., et al. Functional recovery after the systemic administration of mesenchymal
stem cells in a rat model of neonatal hypoxia-ischemia. J. Neurosurg. Pediatr. 22, 467–
599 (2018).

• epilepsy

Fukumura, S., et al. Intravenous infusion of mesenchymal stem cells reduces
epileptogenesis in a rat model of status epilepticus. Epilepsy Res. 141, 56–63 (2018).

• brain tumours

Nakamura, K., et al. Anti-tumor effect of genetically engineered mesenchymal stem cells
in a rat glioma model. Gene Ther. 11, 1155–1164 (2004).

• peripheral neuropathy

Matsuda, Y., et al. Intravenous infusion of bone marrow-derived mesenchymal stem cells
reduces erectile dysfunction following cavernous nerve injury in rats. Sex. Med. 6, 49–57(2018).
Takayanagi, A., et al. Intravenous preload of mesenchymal stem cells rescues erectile
function in a rat model of cavernous nerve injury. J. Sex. Med. 12, 1713–1721 (2015).

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Spinal cord injury: Protocol
The first clinical trial for spinal cord injury using MSC

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MSC intrathecal injection for spinal cord injury

Ref：F. Saito et al. Administration of cultured autologous
bone marrow stromal cells into cerebrospinal fluid inspinal cord injury patients: A pilot study. Restorative
Neurology and Neuroscience 30 (2012) 127-136.
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Mononuclear cell for spinal cord injury

Ref： Suzuki Y, Ishikawa N, Omae K, Hirai T, Ohnishi K, Nakano N, Nishida H, Nakatani T, Fukushima M, Ide C.

Bone marrow-derived mononuclear cell transplantation in spinal cord injury patients by lumbar puncture.
Restor Neurol Neurosci. 2014;32(4):473-82.
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Global expansion of regenerative treatment- Vietnam
Confidential
2012年
12月

ダナン病院 Dr. Ngoc Nguyen
Ba, Dr. Ho Dac Hanh招聘

2013年
7月

ダナン病院訪問し、実行可能性
の検討

2013年
8月

日越友好協会の理事及び副理事とベトナム大使と面談

2014年
2月

ダナン病院、北野病院、先端医療振興財団がMOUの締結

ダナン病院 病院長 Dr. Le Duc Nhan
脳神経外科 Dr. Ngoc Ba Nguyen
北野病院 形成外科部長 鈴木義久
神戸医療産業都市推進機構 尾前 薫

2014年
6月

ベトナム
承認

ダナン市の保健局の

No.

損傷部位

2014年
10月

ベトナム
査察

保健省のダナン病院

年齢・
性別

受傷から移植
までの日数

移植前

6カ月後

1

41男

C5-C6

207

A

2015年
3月・11月2016年
1月

骨髄単核球分離のためのトレー
ニングを北野病院とダナン病院
で実施

2
3

20男
29男

T2-T4
C4-C5

310
109

A
B

4

54男

C2-C4

138

B

B
A
D
C

ASIA

2015年
7月

共同研究契約の締結

5

2015年
11月

ダナン病院での調印式

6

24男

C5-C6

274

A

B

2016年
5月

ベトナム保健省保健大臣承認

7

23男

T8-T10

212

A

B

2016年
9月

第１症例実施(NCT02923817)
日本経済新聞、日本産業新聞、
神戸新聞、ダナン新聞等に掲載

8

20男

C6-C7

125

A

A

9

25男

C4-C5

245

A

2019年
1月21日

第15症例実施

10
11

25男
49男

T2-T8
C3-C4

170
141

A
B

B
B
C

2019/8/6

中 止

Wu Ta-You Science Camp58

Muse Cell
Vol. 540 No.S49, December 7, 2016

Nature Outlook:
Regenerative medicine
www.nature.com/articles/540S49a
Prof. Shinya Minatoguchi
Department of Circulatory and Respiratory Advanced Medicine,
Gifu University Graduate School of Medicine
Prof. Mari Dezawa
Department of Stem Cell Biology and Histology, Tohoku University
Graduate School of Medicine
Publication

Tanaka T., et al.
Mobilized Muse Cells After Acute Myocardial Infarction Predict Cardiac Function and Remodeling in
the Chronic Phase.
Circulation Journal. 2018 ; 82 (2) ; 561-571.

Minatoguchi S., et al.
S1P–S1PR2 Axis Mediates Homing of Muse Cells Into Damaged Heart for Long-Lasting Tissue Repair
and Functional Recovery After Acute Myocardial Infarction.
Circulation Research. 2018;122:1069–1083.

2019/8/6

Wu Ta-You Science Camp59Muse Cell

－intravenous injection of Muse cell for
acute cardiac infarction－

Ref：Minatoguchi S., et al.
S1P–S1PR2 Axis Mediates Homing of Muse Cells Into
Damaged Heart for Long-Lasting Tissue Repair andFunctional Recovery After Acute Myocardial Infarction.
Circulation Research. 2018;122:1069–1083.

2019/8/6

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Critical limb ischaemia

Vol. 548 No.7668_supp, August 24, 2017

Critical limb ischaemia
https://www.nature.com/collections/vmxkcnxvwg/videos
Prof. Atsuhiko Kawamoto
Institute of Medical Research and Development, Translational
Research Center for Medical Innovation, Foundation for Biomedical
Research and Innovation at Kobe, Japan
Publication

Kawamoto, A. et al.
Intramuscular transplantation of G-CSF-mobilized CD34(+) cells in patients with critical limb ischemia:
a phase I/IIa, multicenter, single-blinded, dose-escalation clinical trial.
Stem Cells 27, 2857-2864 (2009).
Kinoshita, M. et al.
Long-term clinical outcome after intramuscular transplantation of granulocyte colony stimulating
factor-mobilized CD34 positive cells in patients with critical limb ischemia.
Atherosclerosis 224, 440-445 (2012).
Fujita, Y. et al.
Phase II clinical trial of CD34+ cell therapy to explore endpoint selection and timing in patients withcritical limb ischemia.
Circ J 78, 490-501 (2014).
2019/8/6

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CLI: G-CSF mobilized autologous peripheral
blood mononuclear cellHorie et al. Outcome from a Randomized Controlled Clinical Trial:
Improvement of Peripheral Arterial Disease by Granulocyte ColonyStimulating Factor-Mobilized Autologous Peripheral-Blood
Mononuclear-Cell Transplantation (IMPACT) .
Circ J. 2018;82(8):2165-74.
2019/8/6

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CLI: G-CSF mobilized peripheral bloodmononuclear cells

Onodera et al. Bone marrow mononuclear cells versus G-CSF-mobilized
peripheral blood mononuclear cells for treatment of lower limb ASO:
pooled analysis for long-term prognosis.
Bone Marrow Transplant. 2011;46(2):278-84.

2019/8/6

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CLI: G-CSF mobilized peripheral bloodmononuclear cells －procedure－Day 1 - 5

Day 5

Day 6

G-CSF
subcutaneous
injection

Magnetic
sorting of
CD34+ cells

Leukapheresis

EPC mobilization
2019/8/6

Total MNCs harvest

Intramuscular injectionof CD34+ cells

EPC purification EPC transplantation

Wu Ta-You Science Camp64

CLI: CD34+ stem cell treatment

Kinoshita et al. Long-term clinical outcome after intramusculartransplantation of granulocyte colony stimulating
factormobilized CD34 positive cells in patients with critical limb
ischemia. Atherosclerosis. 2012;224(2):440-5.
2019/8/6

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CD34+cell treatment for hemodialysis patients

Ohtake et al. Autologous Granulocyte Colony-Stimulating Factor-Mobilized Peripheral
Blood CD34 Positive Cell Transplantation for Hemodialysis Patients with Critical Limb
Ischemia: A Prospective Phase II Clinical Trial.
Stem Cells Transl Med. 2018 Jul 30. [Epub ahead of print]
2019/8/6

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CLI: bFGF + atellocolagen

Ono K et al., First-in-Man Clinical Pilot Study Showing the Safety and Efficacy ofIntramuscular Injection of Basic Fibroblast Growth Factor With Atelocollagen
Solution for Critical Limb Ischemia, Circulation Journal, 2018,
doi:10.1253/circj.CJ-18-0815
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The Principles of Regenerative Medicine
Stem cell therapy and tissue engineering therapy

Preface
Theory: An overview of regenerative medicine: its principles andthe scope of the current revolution
1
Stem Cell Therapy

2
3
4

Tissue Engineering

5
6

2019/8/6

Prof. Honmou,
Spporo medical Univ.

Profs. Minatoguchi & Dezawa,
Gifu Univ. & Tohoku Univ.

Dr. Kawamoto,
TRI

Prof. Kuroda,
Kobe Univ.

Prof. Sotozono,
Kyoto pref. Univ.

Dr. Kanemaru,
Kitano Hosp.
Wu Ta-You Science Camp

Nervous system
Myocardium
Vascular
Bone
CorneaEar drum68Non-union bone fracture: a quicker fix

Vol. 550 No. S193, October 26, 2017

Non-union bone fracture: a quicker fix
https://www.nature.com/collections/qmpthxknbn/videos

Prof. Ryosuke Kuroda
Department of Orthopaedic Surgery, Kobe
University Graduate School of Medicine
Publication
Kuroda R, Matsumoto T, Niikura T, Kawakami Y, Fukui T, Lee SY, Mifune Y, Kawamata S, Fukushima M, Asahara T,
Kawamoto A, Kurosaka M.
Local transplantation of granulocyte colony stimulating factor-mobilized CD34+ cells for patients with femoral
and tibial nonunion: pilot clinical trial.
Stem Cells Transl Med. 2014;3(1):128-34.

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Non-union bone fracture－procedure－

Ref：Kuroda R, Matsumoto T,
Niikura T, Kawakami Y, Fukui
T, Lee SY, Mifune Y,
Kawamata S, Fukushima M,
Asahara T, Kawamoto A,
Kurosaka M.
Local transplantation of
granulocyte colony
stimulating factor-mobilized
CD34+ cells for patientswith femoral and tibial
nonunion: pilot clinical trial.
Stem Cells Transl Med.
2014;3(1):128-34.

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Non-union bone fracture－procedure and result－

Ref：Kuroda R, Matsumoto T, Niikura T, Kawakami Y, Fukui T,
Lee SY, Mifune Y, Kawamata S, Fukushima M, Asahara T,
Kawamoto A, Kurosaka M.
Local transplantation of granulocyte colony stimulating factormobilized CD34+ cells for patients with femoral and tibial
nonunion: pilot clinical trial.
Stem Cells Transl Med. 2014;3(1):128-34.

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Corneal repair

Vol. 544 No.7650_supp_out,April 20, 2017

Corneal repair
https://www.nature.com/collections/pdryjrsvnz/videos

Prof. Chie Sotozono
Department of Ophthalmology, Kyoto Prefectural Universityof Medicine
Publication
Sotozono C, Inatomi T, Nakamura T, Koizumi N, Yokoi N, Ueta M, Matsuyama K, Miyakoda K, Kaneda H, Fukushima M,
Kinoshita S.
Visual improvement after cultivated oral mucosal epithelial transplantation.
Ophthalmology. 2013;120(1):193-200.
Sotozono C, Inatomi T, Nakamura T, Koizumi N, Yokoi N, Ueta M, Matsuyama K, Kaneda H, Fukushima M, Kinoshita S.
Cultivated oral mucosal epithelial transplantation for persistent epithelial defect in severe ocular surface diseases
with acute inflammatory activity.
Acta Ophthalmol. 2014;92(6):e447-53.

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Corneal repair－procedure and result－
Figure 2. Procedure for transplanting cultivated autologous oral
mucosal epithelial sheets. A mucosal specimen containing the oral
mucosal epithelium was collected to create an oral mucosal epithelial
sheet at the Cell Procession Center. After about 2 weeks, thisstratified epithelial sheet was used for cultivated oral mucosal
epithelial sheet transplantation.

Figure 6. Improvement in visual function using limbal rigid contact lenses. A
patient with Stevens–Johnson syndrome with severe adhesion on the ocularsurface and a preoperative vision of counting fingers (0.004). The patient’s own
oral mucosal epithelium transplanted onto the cornea was nearly stabilized 6months after surgery, improving visual acuity to 0.05; the use of limbal rigid
contact lenses further improved visual acuity to 0.9–1.0. This improvement has
been maintained for over 7 years since surgery. (Modified from Ref. 43.)
COMET, cultivated oral mucosal epithelial sheet transplantation
2019/8/6

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Eardrum regeneration: membrane repair

Vol. 546 No.7659_supp, June 22, 2017

Eardrum regeneration: membrane repair
https://www.nature.com/collections/rzfrydkflp/videos
Prof. Shinichi Kanemaru
Department of Otorhinolaryngology/Department of Head and Neck Surgery,Tazuke Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan.
Publication
Omae K, Kanemaru SI, Nakatani E, Kaneda H, Nishimura T, Tona R, Naito Y, Kawamoto A, Fukushima M.
Regenerative treatment for tympanic membrane perforation using gelatin sponge with basic fibroblast growth
factor.
Auris Nasus Larynx. 2017;44(6):664-71.
Kanemaru SI, Kanai R, Yoshida M, Kitada Y, Omae K, Hirano S.
Application of Regenerative Treatment for Tympanic Membrane Perforation With Cholesteatoma, Tumor, orSevere Calcification.
Otol Neurotol. 2018;39(4):438-44.

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Eardrum regeneration－procedure and result－

Ref：Omae K, Kanemaru SI, Nakatani E, Kaneda H, Nishimura T, Tona R, Naito Y, Kawamoto A, Fukushima M.
Regenerative treatment for tympanic membrane perforation using gelatin sponge with basic fibroblast growth factor.
Auris Nasus Larynx. 2017;44(6):664-71.
2019/8/6

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TRI-supported clinical trial：

Eardrum regeneration treatment for tympanic
membrane perforation（US）

2019/8/6

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76

First round of regenerative medicine
has been completed
Type of regeneration

Approved

Nerve

Dec. 20, 2018

(auto serum-expanded
autologous CD105
mesenchymal stem cells)

Approved

Eardrum

Aug. 1, 2019(bFGF/gelatin sponge)

Under trial

Blood vessel

Target Disease
Spinal cord injury

Bone

Shinichi Kanemaru(Kitano Hospital)

Critical Limb Ischemia

Atsuhiko Kawamoto（TRI）

Refractory bone fracture(CD34/atelocollagen)Preparing
NDA

CorneaUnder trial

Cartilage

Ryosuke Kuroda(Kobe University)

Corneal epithelial stem cell deficiency

Chie Sotozono(Kyoto Prefectural
University of
Medicine)

Cartilage injury

Hiroyuki Ishibashi(Hirosaki University)(Mucouse membrane cellsheet)(Cartilage cell/collagen)2019/8/6

Osamu Honmou(Sapporo Medical
University)

Tympanic membrane(CD34/cell)

Under trialPI

Wu Ta-You Science CampSAKIGAKE
Designation★
February
2016

★
March
2018

★
March
2018

77

2nd round of Regenerative Medicine
Development

From Disruptive Innovation
to Continuous Innovation◆ Cell Free
◆ CPC Free
◆ One step preparation technique
2nd round：Clarification of molecular basis of
biological principle concerning tissue generationand establishing its utilization

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Today’s Topics
1. Introduction – we are living in unprecedented
science revolutionary age
2. What kinds of services and supports
TRI provide, and our accomplishments

3. Explore the life/living organisms as it is
4. Principles of regenerative medicine

5. Examples of regenerative medicine－Results from clinical trials
6. What should be done next

2019/8/6

Wu Ta-You Science Camp79Next mission is what should be done next
➢ Next mission is dissemination of regenerative
treatment over the country/world for thepatients waiting, including the process ofinnovation to marketing.

➢ Strategic investment and initiative bygovernment to create an overall
infrastructure to provide regenerative
medicine is critical.

Dramatic reduction of need of care andbedridden
Global expansion
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Regenerative treatment What can be done within next 5 years
日本再興戦略 “Japan revitalization strategy”
Theme１：Extension of healthy life expectancy of citizen・・・・・ ・・・・・59①Society which one can age healthy with effective disease prevention and health control services②Society which can provide cutting-edge medical treatment by activation of medical industry③Society which one can promptly recover to society from disease/injury with the access tohigh-quality medical care
✓

✓

✓

✓

Reduce to just about nil, the bedridden andwheel chaired life caused by spinal cord
injuryReduce to just about nil, the bedridden andcare-needed life caused by stroke
Reduce to just about nil, the lower limb
amputation caused by critical limb ischemia
Reduction ofsocial burden

And much more…

BY adequate medical strategic policy and investment !
2019/8/6

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Grand design of global network
Network management

ECRIN(EU)Global ARO Network Workshop since 2017

AAHRPP
Accreditation

Asia ARO Network
Taiwan-Japan ARO Workshop since 2015

Global ARO Network

ECRIN Data Centre
Certification

NCATS(US)Global development of
academia medical product candidates

CDISC
Standards

Cancer

MCI/AD
ALS
StrokeOthers2019/8/6

Goal

Global“Diseasespecific”
Consortium・Improve Outcomes・Overcome Diseases

Clinical Trial Network
Wu Ta-You Science Camp82

Mission of Academia

1. Academia should live as per science
Science is academia’s soul & spirit
2. To live is to intersect with the world,
to face the world, to work in theworld, and to engage in the world
3. People should live to a high point of
the era, most of all, to live to theheight of philosophy of the era
Misin de la universidad
Jose Ortega y Gasset, 1930
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Our GOAL is total disease control andabsolute improvement of prognosis
We the humans are walking on the road toward total disease
control at last in 2018.
In order to accelerate disease control through medical
innovation, we shall be withdrawing from ineffective
competitive effort driven by researcher’s individual interest.
Desired new concept featuring“Management Science for Science” aim for stableachievements by :- gathering the knowledge and wisdom to gain
synergy effect- through strong project management- bundling medical R&Ds into integrated/synthetic
human science enterprise

Ref: Preface from
“Road to total disease control” by M. Fukushima
Book issued in 20192019/8/6

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謝謝
Thank you for your attention !

2019/8/6

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