Stem cell sheets therapy forpatients with cardiomyopathy

Osaka University
Department of Cardiovascular Surgery

Yoshiki Sawa

Strategy for Heart Failure
Medications
Devices
Operation

LVAS

HTX

Regenerative therapy is desired in the World

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 becommercially available.

A tissue engineered myocardial regeneration
using temperature-responsive culture dishThe culture surface graftedwith N-isopropylacrylamide(temperature-responsiveNIPAAmpolymer)

37℃

Hydrophobic⇒ cell attachment

enzymaticproteolysis(Trypsin)

reducingtemperature<32℃

hydrophilic⇒ cell detachment

lost of almost transplanted cells (80～90%)
myocardial damage by injection needle
 limited therapeutic area by local delivery

Peace-Keeping Design, Osaka University

Tissue engineered cardiac graftSafety and Feasibility study ofregenerative therapy with myoblast sheets
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

NYHA

Administration because ofHeart Failure
Severity of Heart Failure

系列3系列2系列115

pre3.2±0.6

6M

1 year2.2±1.1* 2.0±0.9*

Myoblast implantation

系列4105005

Administration by Heart Failure
1.12 → 0.34 event/year(p<0.01 Wilcoxon signed –rank test)
Cardiac event
0.75 → 0.28 event/pt・year

Survival Curveof severe
heart failure patients
ClinicalOutcomesreceiving myoblast sheets implantation
100%@ 1year
82.5%@ 3years

Cell sheet
SHMSVRPredictablesurvival
curve
植込型VADHTX on waiting
list (Status 2)

Translational Research of autologous myoblast sheet
therapy for severe heart failure patients
2012
Clinical trial for approval (Terumo)

Clinical Study
2007 Clinical study

2004

Pre-Clinical study

Pig model for ICM(Transplantation 2010)
Canine model for DCM(JTCS 2007)

DCM hamstere(JTCS 2006)
Rat model for ICM(JTCS2005,JTCS 2009)

2002 Small animal study
Rat ICM mdel(Transplantation 2005)

2000 Basic Research

Project start (Tissue Eng. 2001)

Number of Heart Failure Patients
introduced to Osaka University Hospitalin 2014

AbroadInternational collaboration and contribution inregenerative therapy with Saudi Arabia

My second visit with ourPrime minister Mr.Abe

Regenerative therapy in Heart
failure patient from Qatar
Before operation

After operation

Dept. Global and Innovativel Medicine, Osaka Univ.

The human resources developmentfor Regenerative medicine
Heart
Temperature-responsive Culture Surface
N-isopropylacrylamide”

37℃
Hydrophobic<32℃
Hydrophilic

LVAS + Myoblast Sheet Transplantation

Bone
Myoblast sheet for Cardiomyopathy by Prof. SawaＭＳＣEye①benign bone
②bone marrow
tumor with large③primary cultureharvestingbone defect(MSC expansion)④MSC integration
to NEOBONE®
differentiation
culture for 2 wks
new bone⑥transplantationof cultured bone

⑤cultured bone(final product)

Bone Tissue Engineering Integrating Novel Ceramic Scaffold
and Mesenchymal Stem Cells by Prof. Yoshikawa

Oral Mucosal Epithelium sheet for Corneal
Reconstruction by Prof. Nishida

iPED2 Cardiac cell sheets show
synchronized beating with heart
タンパク発現維持

Connexin43（+）

Myocardial regeneration therapy
using iPS derived cell sheets
Heart failurepatients
Somatic cell

iPS derivedcell sheet

Oct3/4Sox2

Klf4(c-Myc)

iPS cells

iPS derived cardiac cells

Surface mapping

Skeletal myoblast

iPS derived CMSEF60
5040Control

iPS cell sheet

First POC of iPS cell for heart
failure in the world

30
20n.s.

P=0.0001 P=0.0003

100Baseline 4weeks

8weeksBrentuximab vedotin (AdcetrisTM ) might
eliminate immature iPS cell completely.
hiPSCs-derived cardiomyocyte

qRT-PCR ; the expression level of Lin28= the percent of undifferentiated cell

72 h, 96 h

Brentuximab vedotin (ADCETRIS™)
0, 5, 25 mg/ml% of undifferentiated cell(%)

0.8% of undifferentiated cell

0.7
0.6
0.5

N. S.

0.4

****0.3

†

**

0.2
0.1
0015272 h

25* :P<0.01
vs. 72 h, 0 mg/ml

304596 h
5256mg/ml** :P<0.01† :P<0.05
vs. 96 h, 0 mg/ml
vs. 96 h, 5 mg/ml(ADCETRIS™)

Tumoriogenesis ＝4/5 (Control)
0/8(Adcertis)

Protocol of differentiation from iPS cells into cardiac myocyte

CiRA(Kyoto Univ.) has shipped us
GMP-grade iPS cell For clinical use
Ff-l 01cell

Ff-l 01cell

Ff-l 14cell

Ff-l 14cell

New Regulation for Regenerative Medical Products
under PMDA Act since November 2014
【Standard Pathway of Approval for Drugs and Regenerative Medicinal Products】
ClinicalResearchClinical Trial(confirmation of efficacy and safety)

Approval

OnMarket< 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 ofautologous donor patients【New Pathway for Regenerative Medical Products】
On Market(further confirmationof efficacy and safety)

PMS with Registry of All
Patients

Re-Approval

ClinicalResearch

Clinical Trial Conditional(predict likely efficacy /time-limitedand confirm safety)
marketingauthorization

OnMarketEnsuring the safety of patientswith post-marketing registry

Leading to Earlier Access to patients and Earlier Reimbursement

Japan is now expected its regulation and scientificactivity of Regenerative therapy from the world
Nature Medicine

STEM CELL ACTION AWARD to JSRM

Invitation by USA
Ambassador Ms. Kennedy

Roadmap of Industrializationof Regenerative therapy
iPS cell, cell sheet technology and new regulation are thebreakthrough for new era in regenerative therapy

Market SizeLiverKidney

NeuronRetinaBoneSkinHeart
CorneaCartilage

Allogenic cell

Industrialization

Autologous cell
Clinical application

2015

Years25

Partnership
Which partnership we can do?
We can collaborate each other in thefield of new medical technologies.
We can promote human resource
development including medicalstudents.

Heart failure patients received regenerative
therapy in Osaka University HospitalThank you for your attention !