Takeda-CiRA Joint Program for iPS Cell Applications

Re programm i n g t he F ut ure

Changing the future of healthcare through

regenerative medicine and drug discovery

"I am excited that we will be able to collaborate with CiRA,

the world's leading institute dedicated to pioneering iPS

cell research. "Through this partnership, our company

will provide significant assistance over a long period

to CiRA's research into iPS cell technology applications,

which is a vital part of Japan Revitalization Strategy.

It is our hope to deliver innovative drugs

and cell therapies that meet patient

needs as soon as possible through

this collaboration between

Takeda and CiRA."

"This 10-year joint program with Takeda, Japan's largest

pharmaceutical company, will become a powerful engine

to realize medical applications using iPS cells.

We sincerely thank Takeda's commitment to

iPS cell research. This partnership will

contribute to the development of new

therapies to cure not only major

diseases but also rare ones."

C h r i s t o p h e W e b e r

P r e s i d e n t & C E O , T a k e d a P r o f e s s o r S h i n y a Y a m a n a k a

D i r e c t o r o f C e n t e r f o r i P S C e l l

R e s e a r c h a n d A p p l i c a t i o n ( C i R A ) ,

K y o t o U n i v e r s i t y

CiRA × Takeda =

Combined strengths, high expectations

T -C iR A i s a j o in t r es ea r ch p r o gr a m co n d u cted b y T a k ed a P h a r ma ceu t ica l Co mp a n y a n d

Ky o to U n iv er s i ty ’ s Cen ter fo r iP S Ce l l R es ea r ch a n d A p p l i ca t io n ( C iR A ) . U n t i l n o w,

the lack of br idges l ink ing un ivers i t ies and pharmaceutica l companies in Japan has deterred

a g i le co mmer c ia l i za t io n o f th e r es u l ts f r o m o u ts ta n d in g r es ea r ch co n d u cted a t u n iv er s i t ies .

T -C iRA acts as a b r id ge acr o ss th i s so -ca l led “D eath V a l ley ” o f lo s t o p p o r tu n i ty .

In Europe and the US, venture companies commercia l ize un ivers i ty research and pass i t on to

p h a r ma ceu t ica l co mp a n ies . T -C iR A p r o mis es a s mo o th er r es ea r ch -d ev e lo p men t -co mmer c ia l i za t io n

p r o ces s th r o u gh d i r ect l in k s b etween T a k ed a a n d th e u n iv er s i ty . C iR A a n d T a k ed a a r e co l la b o r a t in g

for 10 years on research into c l in ica l appl icat ions for iPS cel l technologies , a iming to develop

innovative therapies through regenerat ive medic ine and drug d iscovery for use in areas such as heart

fa i lu r e , d ia b etes mel l i tu s , n eu r o -p s y ch ia tr i c d i s o r d er s , ca n cer a n d in tr a cta b le mu s c le d i s ea s es .

The roles of CiRA and Takeda

• T o d i r ect th e r es ea r ch p r o gr a m

• T o p r o v id e iP S ce l l tech n o lo g ies

• T o p r o v id e d r u g d ev e lo p men t ta r gets

a n d a s s a y s y s tems

• T o p r o v id e p r in c ip le in v es t iga to r s ,

r es ea r ch er s a n d p o s td o cto r a l fe l lo ws

〈CiRA〉 〈Takeda〉

• To prov ide co l laborat ive funding of 20 b i l l ion

yen over a 10 -year per iod

• To prov ide more than 12 b i l l ion yen

worth of research support

• To prov ide R&D know -how

• To prov ide research faci l i t ies at Shonan

Research Center

• To prov ide p latform for drug d iscovery

• To prov ide access to compound l ibrar ies

• To prov ide researchers

Concept behind the T-CiRA logo

T h e fo u r co lo r s o f th e lo go s y mb o l i ze th e fo u r gen es

u s ed to in d u ce th e f i r s t ev er iP S ce l l s . T h ey a l s o r ep r es en t

th e in ter act io n amo n g p at ien ts , r esear ch er s , c l in ic ian s

a n d iP S ce l l s . T h e r ed o f th e “T ” i s b o th C iR A ’ s ima ge co lo r

a n d th e s y mb o l co lo r o f T a k ed a . T h e p a p er cr a n e in th e

cen ter o f th e emb lem r ep r es en ts o u r h o p es a n d p r a y er s

for pat ients . The tr ico lor c i rc le embodies the importance of

d iv er s i ty a s we wo r k to geth er to cr ea te in n o v a t iv e

t r ea tmen t o p t io n s .

Booklet Concept

Ju s t a s iP S ce l l s h a v e th e p o ten t ia l to

b eco me a v a r iety o f ce l l ty p es a n d

T -C iR A ca n s h a p e o u r fu tu r e o f

med icat io n , a sh eet o f p ap er can

take on many forms through or igami ,

the art of paper fo ld ing.

We are committed to providing innovative

treatments to patients through iPS cell technology.

At T-CiRA, several novel research projects are underway

for creating medical applications of iPSC,

led by nine principal investigators.

〈ALS dr ug d iscover y

and development using

pat ient-der ived iPSCs〉

Dr. Inoue’s team conducts research into

amyotrophic latera l sc leros is (ALS) ,

a neurodegenerat ive d isease for which

there is no effect ive cure.

They a im to develop new therapeutic

drugs us ing pat ient -der ived iPSCs and

Takeda's compound l ibrar ies .

〈R e s e a r c h o n C e l l T h e r a p y

against Type 1 Diabetes〉

D r . T o y o d a 's tea m i s co n d u ct in g r es ea r ch

in to ce l l th er a p y a ga in s t ty p e 1 d ia b etes

mel l i tus involv ing transp lants of

iP SC -d er iv ed p a n cr ea t i c ce l l s .

Their current research a im is to develop

new treatments based on is let

transp lantat ion, but without the current

l imitat ions of such transplantat ion.

Clinical-grade iPS cells

Differentiation

Pancreatic cells

Encapsulation

I n s u l i n Im m une cel l s

Implantation

Type1 Diabetes patients

Haruhisa Inoue

Taro Toyoda

iPS cel ls

D i f fere n t ia t io n

Endocr ine cel l c lusters

Insulin G lucagon Nucle i

Yoshinori Yoshida Shin Kaneko

Red : cardiac troponin T

Differentiation and

maturation

iPSC Mixture of CMs

Purif ication with miRNA-switch, etc .

Disease modeling Ventricular

CMs

Compounds /gene Therapeutic targets

Cell therapy

Factory

HLA homozygous iPSC derived from Super-donors

tumor antigen-specif ic , rearranged TCR gene

HLA homozygous iPSC harboring antigen-specif ic TCR gene

HLA-matched patients

iPSC-derived T-cells

self-renewal

TCR introduction

self-renewal

Differentiation and expansion

T-cell infusion Cell bank

Hospital

▶ T cel l receptor (TCR) gene that targets

cancer cel ls i s introduced into iPSCs der ived

from super donors , which can prov ide a

match for a large populat ion of pat ients .

▶ T-cel ls are d i f ferentiated from iPSCs,

mass-cu ltured and stocked us ing

manufactur ing methods industr ia l ized and

standard ized.

▶ The stockpi led T cel ls can be admin istered

t o H L A - m a t c h e d c a n c e r p a t i e n t s a n d a

marked therapeutic ef fect can be expected

on cancers express ing the relevant antigen.

▶ Human iPSCs are d i f ferentiated into card iomyocytes (CMs) , which are then matured.

▶ Su b p o p u la t io n s o f ca r d io my o cy tes , s u ch a s

ventr icu lar card iomyocytes , are select ively

a cq u i r ed f r o m iP SC -d er iv ed ce l l s wi th

v a r ied ch a r a cter i s t i cs u s in g miR NA -s wi tch

a n d o th er tech n iq u es . T h es e ce l l s a r e u s ed

fo r ce l l th er a p y a n d co mp o u n d s cr een in g .

Dr . Yosh ida 's team aims to create

iPSC-der ived card iomyocytes su itab le for

regenerat ive therapy and drug d iscovery

research us ing new technologies such as

microRNA-switch technology developed at C iRA.

With these card iomyocytes ,

they a im to develop cel l therap ies against

heart fa i lure a longs ide next -generat ion

drug d iscovery p latform and

new therapeutic drugs .

〈Development of an iPSC-based drug

discovery platform and application to

novel therapy for heart failure〉

Dr. Kaneko's team is try ing to develop

a novel cancer immunotherapy

using iPSC-der ived immune cel ls .

We asp ire to rea l ize "off - the-shelf"

a l logeneic products for cancer pat ients

by combin ing CiRA's human iPS cel l

s tock for regenerat ive medic ine with Takeda's

exper ience in drug production.

〈Development of a novel

immunotherapy using iPSC-derived

cancer antigen-specific T-cells〉

Hidetoshi Sakurai Akitsu Hotta 〈Drug discovery for

intractable muscular disease

using patient-derived iPSCs〉

D r . Sa k u r a i ' s tea m wi l l c r ea te n o v e l th er a p eu t ic

d r u gs fo r in tr a cta b le mu s cu la r d i s ea s es s u ch a s

mu s cu la r d y s tr o p h y a n d in v es t iga te

mu s cu la r d i s ea s e mo d els . T o a ch iev e th i s go a l ,

th ey wi l l u t i l i ze p a t ien t -d er iv ed iP SCs

a s a to o l fo r d i s ea s e mo d el in g a n d

d r u g s cr een in g .

〈Therapeutic genome editing for

congenital muscular dystrophy〉

D r . Ho tta ’ s tea m a ims to co r r ect th e ca u s a l

gen et ic mu ta t io n s in v o lv ed in s ev er e

mu s cu la r d y s tr o p h y u s in g s ta te -o f - th e-a r t

gen o me ed i t in g a n d d e l iv er y tech n o lo g ies .

T h e tea m a ims to d ev e lo p p r o p r ieta r y

tech n o lo gy th a t wi l l en a b le th em to cr ea te

n ew gen e th er a p ies wh i le , a t th e s a me t ime,

co n f i r min g r ep a i r e f f i c ien cy an d sa fety

u s in g p a t ien t -d er iv ed iP S ce l l s .

▶ Bo th iP S ce l l s d er iv ed f r o m h ea l th y s u b j ects

and patients are d i f ferentiated into skeleta l

muscle cel ls on 384 -wel l p lates .

▶ A h igh-throughput drug screening

evaluat ion system is developed by v isual iz ing

pathologica l changes observed only in

pat ient-der ived skeleta l muscle cel ls .

▶ Co mp o u n d s th a t imp r o v e p a th o lo g ica l

ch a n ges a r e s e lected a n d o p t imized .

Control iPSCs Patient iPSCs

Control Myocytes

Differentiation

Patient Myocytes

Modeling Disease Phenotype

Drug screening for altering disease phenotype

Muscle cells

384 well plate

Patient iPSCs

Differentiation

Patient Myocytes

Dystrophin mRNA

STOP

No dystrophin

Patient’s myocytes Restored myocytes

"Genome Surgery"

Exon skipping

Dystrophin +

▶ E v en wh en p a t ien t -d er iv ed iP S ce l l s ,

which harbor a genetic mutat ion in the

dystrophin gene, are d i f ferentiated into

skeleta l muscle cel ls , dystrophin protein

express ion is absent.

▶ By us ing genome edit ing technology to

sk ip exons that carry a genetic mutat ion,

i t i s poss ib le to rescue the express ion of

dystrophin protein that reta ins some degree

of funct ional i ty .

Takanori Takebe Makoto Ikeya 〈Miniature liver technology

as a platform for research towards

pharmaceutical applications〉

Based o n h u man iPSC -d er iv ed min ia tu r e l i v er

tech n o lo gy d ev e lo p ed a t Y o k o h a ma C i ty U n iv er s i ty ,

D r . T a k eb e’ s tea m i s d ev e lo p in g a in n o v a t iv e

s y s tem th a t ca n r ep r o d u ce th e co mp lex

p h en o men a fo u n d wi th in p a t ien ts ’ b o d ies .

T h i s r es ea r ch wi l l c r ea te a n o v e l d r u g d i s co v er y

s y s tem fo r in tr a cta b le d i s ea s es a n d a n o v e l

p r ed ict iv e p la t fo r m fo r exp r es s io n a n a ly s i s o f

r a r e a d v er s e ev en ts u n fo r es een in t r a d i t io n a l

d r u g d i s co v er y r es ea r ch .

〈A new research platform with human

iPSC-derived neural crest cells and

its applications for drug discovery

and regenerative medicine〉

Neu r a l c r es t ce l l s d i f fer en t ia te in to d iv er s e ce l l ty p e

l in ea ges s u ch a s b o n es a n d p er ip h er a l n eu r o n s ,

s u gges t in g th e i r g r ea t p o ten t ia l fo r c l in i ca l

a p p l i ca t io n s . D r . I k ey a ’ s tea m a ims to cr ea te meth o d s

to ma in ta in cu l tu r es o f h u ma n iP SC -d er iv ed n eu r a l

c r es t s tem ce l l s a n d to in d u ce th em to d i f fer en t ia te

in to v a r io u s ty p es o f ce l l s . M o r eo v er , th ey h o p e to

co n str u ct an in vitro d isease mo d el in co mb in at io n

with r e la ted tech n o lo g ies a n d a p p ly i t to d r u g

d ev e lo p men t a n d r egen er a t iv e med ic in e .

▶ Genomic information is used for the strategy to

create iPSCs that al lows the team to establish a

method of screening donors that could be useful

for predicting the phenotype of rare diseases.

▶ Furthermore, by creating a mini - l iver consisting

of multiple types of cel ls , the team wil l construct

a method to reproduce complex patient pathology

in vitro.

▶ By integrating these two proprietary methods of

genome research and cellome research, the team

will contr ibute to the creation of an innovative

drug discovery system.

▶ Neural crest cel ls are a un ique cel l

populat ion that ex ists on ly in the ear ly

stages of development. Much about them

remains unknown, especia l ly human neural

crest cel ls .

▶ It is very difficult to cultivate neural crest

cells in vitro while maintaining their

u n d i f fer en t ia ted s ta te . Bu t i f b a s ic

tech n o lo g ies to ma in ta in n eu r a l c r es t ce l l s

ca n b e es ta b l i s h ed u s in g h u ma n iP SCs ,

th e a p p l i ca t io n p o s s ib i l i t ies a r e exten s iv e .

Disease patients Healthy populations

Cellomics Genomics

iPSC

Maturation

Miniature Liver

Multifactorial Disease Modeling

Mu

lti-cellu

lar

org

an

izatio

n

Drug discovery Predict DILI

DILI : Drug-induced l iver injury

D r u g d i s c ov e r y C e l l t h e r a p y

h u m a n i P S c e l l s

N e u r a l c r e s t s t e m c e l l s

S e l f - r e n e w a l D i f f e r e n t i a t i o n

P e r i p h e r a l n e u r o n s S t r o m a l c e l l s

D i f f e r e n t i a t i o n Differentiation

Reprogramming the Future

Reprogramming the future of l i fe sc ience,

medic ine and our patients

Tadashi Suzuki 〈Development of therapeutic

agents for rare hereditary

diseases using iPS cells〉

D r . Su zu k i ' s tea m i s fo cu s in g o n a d ef i c ien cy

in th e NG LY 1 gen e th a t en co d es fo r

th e d e-N -g ly co sy la t in g en zy me N -g ly can ase .

T h ey wi l l d ev e lo p in n o v a t iv e th er a p eu t ics fo r

NG LY 1 d ef i c ien cy , a r a r e in h er i ted d i s ea s e

th a t p r es en t ly d o es n o t h a v e a n y th er a p eu t ic

o p t io n s , th r o u gh a co mb in a t io n o f b a s ic

r es ea r ch f in d in gs , iP SC tech n o lo gy a n d

a d r u g d i s co v er y p la t fo r m.

ER Cytoplasm

N-Glycan

Lysosomal degradation

Misfolded glycoprotein

NGLY1-deficiency

Proteasomal degradation

* NGLY1

*Key enzyme in -glycan degradation pathway (T. Suzuki, Sem. Cell Dev. Biol. 2007)

DISEASE

NGLY1 deficient iPSCs & mice as research platforms for therapeutic options

N-GlcNAc proteins (abnormal protein?)

Key Research Platform Clinical information

Patient-derived iPSCs

Ngly1-KO mice w/ Physicians &

Patients’ Foundation

Disease modelling

Therapeutic options

・Strategy for therapeutics ・Reproduction of disease-specific phenotype

・Assay system for drug screens ・Biomarkers for diagnosis & efficacy

・Existing & repositioning drugs ・Enzyme replacement

・Gene delivery

Giving

shape to hopes

– with agility

Cutt ing-edge technology leads

our center for drug creation

T h e T - C i R A r e s e a r c h l a b o r a t o r y h a s b e e n

es ta b l i s h ed a t th e Sh o n a n R es ea r ch Cen ter

a s a b r a n ch o f C iR A . Her e , o v er 100

r es ea r ch er s f r o m C iR A , Y o k o h a ma C i ty

Univers i ty , R IKEN and Takeda work together

us ing iPS cel l technologies .

The lab features the latest equipment and

r e s o u r c e s , c r e a t i n g a o n e - s t o p r e s e a r c h

env ironment that begins with fundamental

research and cu lminates in research for

c l in ica l tr ia l appl icat ions.

① T a k ed a ’ s Sh o n a n R es ea r ch Cen ter ,

Ka n a ga wa , Ja p a n

② A r es ea r ch er u s in g a micr o s co p e

③ T h e la tes t in s ta te -o f - th e-a r t h igh -co n ten t

s cr een in g d ev ices , a l lo win g fo r s imu l ta n eo u s

h igh - r es o lu t io n p h o to gr a p h y

a cr o s s fo u r wa v e len gth s

④ FA CS eq u ip men t d i r ects a laser o n to

th e s u r fa ce o f a f lu o r es cen t a n t ib o d y -s ta in ed

ce l l to mea s u r e i t s a n t ib o d y lev e l s

⑤ T -C iR A r es ea r ch er s ’ r o o m fo r d es k wo r k

⑥ High - th r o u gh p u t s cr een in g d ev ices u s ed to

u n ea r th th e s eed s o f d r u g d i s co v er y

f r o m co mp o u n d l ib r a r ies

⑦ A c lea n b en ch wh er e r es ea r ch er s f r o m

C iR A a n d T a k ed a wo r k s id e b y s id e

In order to foster a sense of unity among those

engaged in our T-CiRA research activities,

a total of 122 T-CiRA researchers and T-CiRA

support members came together at the T-CiRA

Retreat.

The participating researchers gave oral and

poster presentations and deepened their

understanding of mutual projects through

spirited discussion.

A morning run with Prof. Yamanaka was also

planned. We shared our desire with him to

complete the long road to applying iPS cell

research to drug discovery.

Every month, Prof. Yamanaka visits the Shonan

Research Center and participates in the T-CiRA

monthly meeting. At the meeting, a serious

discussion takes place on individual project

plans and their progress, in order that treatment

methods derived from iPSC research can be

realized as soon as possible.

Together with our partners,

towards the future of drug discovery

Mr. Matt Wilsey (representative of the Grace

Science Foundation, an NGLY1 deficiency patient

group) visited T-CiRA. He expressed his hope

that T-CiRA can provide innovative new drugs

to patients suffering from intractable diseases

without established effective treatments.

〈T - C i R A R e t r e a t〉

〈T-C iRA Month ly Meet ing〉

〈Visit of a patient group representative〉

Printing / Broadcast Date

〈Articles and programs on T-CiRA〉 Printing / Broadcasting Program Printing / Broadcast Date

Printing / Broadcasting Program

January 25, 2016

March 5, 2016

June 11, 2016

August 25, 2016

October 24, 2016

Yomiuri Shimbun

Yomiuri Shimbun

Diamond Weekly

Mainichi Shimbun

Kansai Joho Netto ten.

(Yomiuri Television)

October 27, 2016

January 2, 2017

February 14, 2017

February 21, 2017

February 21, 2017

March 15, 2017

April 13, 2017

The Chemical Daily

Nikkei Biotech ONLINE

Nikkan Kogyo Shimbun

Nikkan Kogyo Shimbun

The Chemical Daily

Kyoto Shimbun

The Cambrian Palace

(TV Tokyo series) (As of April, 2017)

P r o f . Sh in y a Y a ma n a k a p u b l i s h ed es ta b l i s h men t o f a mo u s e iP S ce l l l in e

P r o f . Sh in y a Y a ma n a k a p u b l i s h ed es ta b l i s h men t o f a h u ma n iP S ce l l l in e

Cr ea t io n o f d i s ea s e -s p ec i f i c iP S ce l l s b ega n

I n i t ia l p a ten t gr a n ted in Ja p a n fo r c r ea t io n o f iP S ce l l s

T h e Cen ter fo r iP S Ce l l R es ea r ch a n d A p p l i ca t io n , Ky o to U n iv er s i ty wa s es ta b l i s h ed

D iv i s io n fo r iP S Ce l l C l in i ca l D ev e lo p men t es ta b l i s h ed a t Ky o to U n iv er s i ty Ho s p i ta l

P a ten ts o b ta in ed in th e U S a n d E u r o p e fo r c r ea t io n o f iP S ce l l s

P r o f . Sh in y a Y a ma n a k a wa s a wa r d ed th e No b el P r i ze in P h y s io lo gy a n d M ed ic in e

R I KE N’ s M a s a y o T a k a h a s h i led c l in i ca l r es ea r ch u s in g h u ma n iP S ce l l s , d u r in g wh ich a

t r a n s p la n t s u r ger y wa s co n d u cted

Sh ip men t o f iP S ce l l s to ck fo r r egen er a t iv e med ic in e u s e b ega n

T -C iR A Jo in t P r o gr a m fo r iP S Ce l l A p p l i ca t io n s b ega n

Stem cell research began on somatic stem cells and mouse ES cel ls

iPS cell research began with a focus on neuronal differentiation, pancreatic β cel l

d ifferentiation and cardiomyocyte differentiation

Prof. Shinya Yamanaka provided two kinds of human iPS cel l clones to Takeda

Takeda participated in the Advanced Medical Development Project (a Japan’s

National project ) led by Prof. Shinya Yamanaka: “Project to Accelerate Medical

Applications of iPS Cells”

Disease-specif ic iPS cel ls were introduced and fundamental research on

regenerative medicine (pancreatic β cel ls , nerve cel ls) began

Takeda conducted joint research with Prof. Haruhisa Inoue of CiRA on iPS cel ls

derived from patients with Alzheimer’s and ALS

Takeda conducted joint research with Prof. Kenj i Osafune of CiRA on

insulin-producing cel ls using iPS cel ls

Various differentiated cel ls and human disease models created

Takeda participated in the National project "Application of disease -specif ic iPS

cel ls for intractable diseases"

T-CiRA Joint Program for iPS Cell Applications began

A Hi story of i PS Ce l l Researc h at C i RA

A Nobel Prize

was only the beginning

A brighter future for patients through

innovative new treatment options

A Hi story of Stem Cel l Researc h at Takeda

2006

2007

2008

2010

2011

2012

2014

2015

2006

2008

2010

2011

2012

2013

2014

2015

T -C iR A ta k es a n o v e l a p p r o a ch to wa r d t r ea tmen ts o f p a t ien ts wh o wer e p r ev io u s ly

without effect ive therapeutic options. Our pro jects are progress ing rap id ly ,

u s in g th e p o wer o f iP S ce l l s to fo r mu la te n ew th er a p eu t ic o p t io n s .

Working c losely together , un ivers i ty and pharmaceutica l industry

r es ea r ch er s a r e ma p p in g u n ch a r ted ter r i to r y to d i s co v er

in n o v a t iv e s o lu t io n s . T a k e th e ca s e o f A my o tr o p h ic

La ter a l Sc ler o s i s ( A LS) a fa ta l n eu r o d egen er a t iv e d i s ea s e .

I f o u r d r u g s cr een in g fo r th i s d i s ea s e s u cceed s ,

th e n er v e d egen er a t io n th a t ca u s es th e d i s ea s e

could be halted entirely . S imi lar ly , i f a pro ject to

cr ea te in s u l in -s ecr et in g p a n cr ea t i c β ce l l s s u cceed s ,

pat ients suffer ing from d iabetes mel l i tus may

no longer need insu l in in ject ions. Our dream

i s that pat ients wi l l receive therapeutic

options d iscovered d irect ly through

our 10-year co l laborat ive

r es ea r ch ef fo r t .

Univers i ty and Pharmaceutical working

hand in hand - to solve unprecedented chal lenges.

2025 – The year new therapies will become reality

Reprogramming the Future

h t t p s : / / w w w . t a k e d a . c o m / T - C i R A /

Delivering innovative therapeutic options to our patients,

as soon as possible. That ’s our mission, every day.

Se i g o I z u m o

G l o b a l H e a d

R e g e n e r a t i v e M e d i c i n e U n i t