Stem cell sheets therapy for patients with cardiomyopathy

Yoshiki Sawa

Osaka University

Department of Cardiovascular Surgery

Medications

DevicesOperation

LVAS

HTX

Strategy for Heart Failure

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 be commercially available.

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

Tissue engineered cardiac graft

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

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*

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

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

Abroad

Number of Heart Failure Patients introduced to Osaka University Hospital

in 2014

再生医療の国際医療貢献

International collaboration and contribution in regenerative 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 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

2 Cardiac cell sheets show synchronized beating with heart

Connexin43（+）

タンパク発現維持

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)

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

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™)

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

【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

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

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

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.

Heart failure patients received regenerative therapy in Osaka University Hospital

Thank you for your attention !