Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical...
Transcript of Stem cell sheets therapy for patients with cardiomyopathy...marketing authorization Clinical...
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Stem cell sheets therapy for patients with cardiomyopathy
Yoshiki Sawa
Osaka University
Department of Cardiovascular Surgery
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Medications
DevicesOperation
LVAS
HTX
Strategy for Heart Failure
Regenerative therapy is desired in the World
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Stem cell therapy for heart failure
Bone Marrow(RepairAMI)
Endothelial progenitor cell
Skeletal muscle cell(MagicTrial)
Mesenchymal stem cell
Cardiac stem cell (SCIPIO Trial)
No protocol can be commercially available.
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Peace-Keeping Design, Osaka University
The culture surface grafted with N-isopropylacrylamide(temperature-responsive polymer) NIPAAm
<32℃37℃Hydrophobic hydrophilic
⇒ cell attachment ⇒ cell detachment
A tissue engineered myocardial regeneration using temperature-responsive culture dish
enzymaticproteolysis (Trypsin)
reducing temperature
lost of almost transplanted cells (80~90%)
myocardial damage by injection needle
limited therapeutic area by local delivery
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Tissue engineered cardiac graft
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Indications: End stage of DCM patients under LVAS who indicate heart transplantation
Endpoint: to clarify its safety and feasibility
Secondary endpoints: evaluate cardiac function
Case number:6
Study periods:2years
Safety and Feasibility study of regenerative therapy with myoblast sheets
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051015
Administration because of Heart Failure
0 5
Myoblast im
plantation
Administration by Heart Failure 1.12 → 0.34 event/year(p<0.01 Wilcoxon signed –rank test)
Cardiac event0.75 → 0.28 event/pt・year
系列4 系列3
系列2 系列1
NYHASeverity of Heart Failure
pre 6M 1 year
3.2±0.6 2.2±1.1* 2.0±0.9*
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植込型VADSVR
Clinical Outcomes
100%@ 1year82.5%@ 3years
HTX on waiting list (Status 2)
Cell sheetSHM
Predictable survival curve
Survival Curve of severe heart failure patients receiving myoblast sheets implantation
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Translational Research of autologous myoblast sheet therapy for severe heart failure patients
Project start
Rat ICM mdel(Transplantation 2005)
Rat model for ICM(JTCS2005,JTCS 2009)
DCM hamstere(JTCS 2006)
Canine model for DCM(JTCS 2007)
Pig model for ICM(Transplantation 2010)
Pre-Clinical study
Basic Research
Clinical Study
Small animal study
Clinical study
(Tissue Eng. 2001)
Clinical trial for approval (Terumo)2012
2007
2004
2002
2000
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Abroad
Number of Heart Failure Patients introduced to Osaka University Hospital
in 2014
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再生医療の国際医療貢献
International collaboration and contribution in regenerative therapy with Saudi Arabia
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My second visit with ourPrime minister Mr.Abe
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Regenerative therapy in Heart failure patient from Qatar
Before operation
After operation
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Dept. Global and Innovativel Medicine, Osaka Univ.
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The human resources development for Regenerative medicine
Heart
Eye
Bone
LVAS + Myoblast Sheet Transplantation
<32℃37℃Hydrophobic Hydrophilic
Temperature-responsive Culture Surface
N-isopropylacrylamide”
Myoblast sheet for Cardiomyopathy by Prof. SawaMSC
new bone
①benign bone tumor with large bone defect
②bone marrowharvesting ③primary culture
(MSC expansion)
④MSC integration to NEOBONE®
differentiationculture for 2 wks
⑤cultured bone (final product)
⑥transplantation of cultured bone
Bone Tissue Engineering Integrating Novel Ceramic Scaffoldand Mesenchymal Stem Cells by Prof. Yoshikawa
Oral Mucosal Epithelium sheet for Corneal Reconstruction by Prof. Nishida
iPED
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2 Cardiac cell sheets show synchronized beating with heart
Connexin43(+)
タンパク発現維持
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Heart failure patients iPS cells
Somatic cell
iPS derived cardiac cellsiPS derived cell sheet
Myocardial regeneration therapy using iPS derived cell sheets
Oct3/4 Sox2
Klf4 (c-Myc)
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Control iPS cell sheet
0
10
20
30
40
50
60
P=0.0001
EF
n.s. P=0.0003
Baseline 4weeks 8weeks
First POC of iPS cell for heart failure in the world
Surface mapping
Skeletal myoblast iPS derived CMS
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Brentuximab vedotin (AdcetrisTM ) might eliminate immature iPS cell completely.
Brentuximab vedotin (ADCETRIS™)0, 5, 25 mg/ml
72 h, 96 hhiPSCs-derived cardiomyocyte
Brentuximab vedotin reduced the number of undifferentiated cells
* :P<0.01vs. 72 h, 0 mg/ml
** :P<0.01vs. 96 h, 0 mg/ml
% of undifferentiated cell
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
1 2 3 4 5 6
% o
f u
nd
iffe
ren
tiat
ed c
ell
(%)
0 5 25 mg/ml0 5 2572 h 96 h
* ***
**
N. S.
†
† :P<0.05vs. 96 h, 5 mg/ml
qRT-PCR ; the expression level of Lin28= the percent of undifferentiated cell
Tumoriogenesis =4/5 (Control)
0/8(Adcertis)
(ADCETRIS™)
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Protocol of differentiation from iPS cells into cardiac myocyte
Ff-l 01cell
Ff-l 01cell Ff-l 14cell
Ff-l 14cell
CiRA(Kyoto Univ.) has shipped us GMP-grade iPS cell For clinical use
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【New Pathway for Regenerative Medical Products】
New Regulation for Regenerative Medical Products under PMDA Act since November 2014
Clinical Trial(confirmation of efficacy and safety)
ApprovalClinical
Research
On Market(further confirmationof efficacy and safety)
PMS with Registry of All Patients
Conditional /time-limited
marketing authorization
Clinical Research
On Market
On Market
Clinical Trial(predict likely efficacy
and confirm safety)
Re-A
pp
roval
< Drawback of traditional PAL approval system > Long-term data collection and evaluation in clinical trials is not suitable for cellular/tissue-based products
because of non-uniform quality reflecting individual heterogeneity of autologous donor patients
Ensuring the safety of patients with post-marketing registry
【Standard Pathway of Approval for Drugs and Regenerative Medicinal Products】
Leading to Earlier Access to patients and Earlier Reimbursement
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Nature Medicine STEM CELL ACTION AWARD to JSRM
Invitation by USA Ambassador Ms. Kennedy
Japan is now expected its regulation and scientific activity of Regenerative therapy from the world
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25
Roadmap of Industrialization of Regenerative therapy
Autologous cellSkinBone
Cornea
Neuron
Heart
Retina
Liver
Kidney
Mar
ket
Siz
e
Years2015
iPS cell, cell sheet technology and new regulation are the breakthrough for new era in regenerative therapy
Allogenic cell
Cartilage
Clinical application
Industrialization
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Partnership Which partnership we can do?
We can collaborate each other in the
field of new medical technologies.
We can promote human resource development including medical
students.
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Heart failure patients received regenerative therapy in Osaka University Hospital
Thank you for your attention !
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