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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