Workshop on Regenerative Medicine/Stem Cells

Round Table Meeting

Health, care and welfare technology

June 7th, 2018, Tokyo, Japan

Kamal Mustafa, University of Bergen

Yasuhiko Tabata, Kyoto University

Stem Cells in Clinical trials – June 2018

• 6673 registered studies ”stem cells” US National

Institutes of Health www.clinicaltrials.gov

• 843 - Bone marrow Mesenchymal stem cells

• 274 - Adipose stem cells

• 52 - Dental stem cells

• 49 – Embryonic stem cells

• The social and psychological handicap of persons

having substantial bone defect or neurological

diseases has a tremendous impact on society in

Japan or in Norway

• Restructuring portions of the human anatomy has

long been the goal of reconstructive medicine

Multiple sclerosis (MS) – Diseaseseverity and cost

• Inflammatory disease of the CNS

• Genetic and environmental risk factors

• MS-attack: 30-50 % with no complete remission

• 7 years reduced life expectancy

• The total economic cost of MS was in 2010

estimated at €14.6 billion for Europe alone

Properties of MSCs and bone marrowderived cells

• Angiogenesis

• Suppression of inflammation, immune modulation

• Neuroprotection

• Cell fusion

MSC transplantation in MS

• Feasibility and safety

• Autologous culture-expanded BM MSCs• Bonab et al. 2007,2012 (IT)

• Cohen et al. 2017 (IV)

• Connick et al. 2012 (IV)

• Karrussis et al. 2010 (IT+IV in five)

• Llufriu et al. 2014 (IV)

• Odinak et al. 2011 (IV)

• Yamout et al. 2010 (IT)

MSC transplantation in MS

Proposed Japan/Norway cooperative project

• Japanese groups

– Prof. Minoru Ueda (Nagoya)

• Norwegian groups:

– Prof. Lars Bø (aHSCT-group, UiB

– Prof. Kjell-Morten Myhr (Neuro SysMed, UiB)

– Prof. Kamal Mustafa, (Tissue Engineering group,

UiB

• Italy: Dr. Rosaria Giordano, Milan Hospital

• Germany: Prof. Hubert Schrezenmeier, ULM

University

MSC: Issues of clinical trials

• Source of MSC

• Optimal dose of MSC

• Expansion and avoiding loss of reparative and neuroprotective effects

• Mixed/unseparated cells or purified and culture expanded MSC

• Predifferentiated MSC?

Gold standard treatment

• 2nd most commonly transplanted

tissue

• 2.2 million grafts per year globally

2.5 billion/yr Kinaci A et al. 2014, Giannoudis PV et al. 2005, Blausen.com staff. "Blausen gallery 2014"

Autogenous bone grafts

Condition medium from Hypoxia promoted DO healing through

blood vessel regeneration

Masahito F, Yamamoto A, Hibi H, Ueda M, Fristad I, Mustafa K. J Tissue Eng Regen Med. 2015.

Cecilie Gjerde

Regenerating bone defects using MSC

and biomaterial as a new approach

• UiB; Faculty of Medicine is the sponsor for 2 multicentre trials

13

Bone biopsies

Pre-augmentation 6 month after augmentation

Cast of alveolar ridge before and after augmentation illustrating the amount of bone reconstructed

uib.no14

First clinical trial and among few trials in Europe

23-24042015 15

Patient 04

In spite of very limited blood supply because of area (posterior mandibula) and the membrane

The results are very good!

23-24042015 16

• 2nd Trial involving reconstructing of:–Cleft palate

uib.no

Bergen Research

Foundation (BFS)

With great expectations for the future of stem cells

• Increase number of patients (200)• Phase II/III clinical trial

uib.no

Clinical Study B – Orthopaedic clinical trial

in long bones:

- Traumatic isolated open fractures with a

bone

defect of 2 – 10 cm

- Bone loss of 2 – 10 due to prior infection

and/or non-vascularized bone

- 10 patients in total

- 2017/278/REK vest: Reparasjon av

beindefekter

i lange rørknokler ved bruk av stamceller

Conditioned Medium （CM）

CM contain a lot of growth factors!

Prof. Minoru Ueda, Nagoya University, Japan

Control SHED-CM

Recovery of hind limbs

Representative Case

• Patient : 60-y-old male ( chronic stage )

• History : 2015/6 : Left Cerebral infarction

Sever disfunction in right

hand and foot

2015/8 : Start of rehabilitation

2017/6 : No remarkable improvement

2017/7 : Transnasal administration

of SHED-CM, X28

21

Before Treatment

2 years after CI

(60 F)

Before treatment

2 years after CI( 60 F )

4 weeks 60 F CI

4 weeks 60 F CI

Scaffolds

• Temporary structural

support

• Cellular microenvironment

– High surface area

– Facilitate cell migration

– Extracellular matrix secretion

• Release control of molecules

and growth factors

Cell culture

Cell culture

Sponge shrinkage during cell culture because of poor mechanical strength of sponge

drawback

shrinkage

shrinkage

Non-shrinkage scaffold

collagen sponge

collagen sponge reinforced

A representative 3D-scaffold compatible to cells

The collagen sponge reinforced by PLLA fibers and beta-TCP granules

It is important in cell-based regenerative therapy for efficient

proliferation of stem cells

Preparation of mechanically reinforced scaffold

Prof. Yasuhiko Tabata

The in situ migration of neural cells in brain was

enhanced by the local release of HGF,

Nakaguchi et al. 2012

Bone regeneration by dual release of SDF-1 and

BMP-2 in the defects, Biomaterials 32 (2011)

uib.no

Department of Clinical Dentistry

29

Develop an innovative, biodegradable hydrogel bio-ink to fit

the requirements of the 3-D printing technology

Large collaborative projects between Norway-Japan

Scaffold (matrix) production, characterization,

functionalization with MSC, CM, GF

Oral/maxillofacial bone

preclinical/clinicalLong bone

preclinical/clinical

Transnasal delivery

- Preclinical studies

- Clinical Trials

1. MS

2. ALD

3. CI (chronic)

Collaboration: Mc Cormack lab – Heissig lab

Understanding the leukemic environment: potential for drug testing

Goal:- Establish stable humanized AML and MDS in mice - To understand the function of niche cells in a dimensional defined setting- To find novel drug targets- To validate candidate drug targets

Procedure: 1) Collection and exchange of human acute leukemia and MDS samples between both countries

(Collaboration Prof. Takahashi, Dept. Haematology and Transplantation medicine, IMSUT and Prof.Hattori, Dept. of Regenerative Medicine, Juntendo University

2) In Norway: Receiving the leukemic patient samples and establish stable leukemic cells from each patient (AML material)

3) In Japan and Norway: receiving the stable AML material for drug testing in vivo and in vitro 4) Use material like plasma from these mice to find novel drug targets (Prof. Heissig, IMSUT )

Project Proposal:

Screening and pre-clinical testing of new drugs to treat MDS/AML

Kitamura/Goyama lab

Initial screening to identify candidate drugs for MDS and AML

using murine models of MDS/AML

(days)

(%)

Surv

ival

p<0.0001

Control

Drug A

% S

urv

ival

p=0.0007

(days)

Control

Drug B

Examples of candidate drugs

Mc Cormack lab

Confirmation of the effect of the candidate drugs using PDX models of MDS/AML

(Collaboration between Kitamura/Goyama Lab and Mc Cormack lab)

Competence:

• Kyoto Univers – Prof. Yasuhiko Tabata (hydrogel, innovation)

• Nagoya Univers – Prof. Minoru Ueda (CM, MSC, CI)

• Hokkaido Univers – Dr. Masahito Kawabori (CI)

• Kyoto Women University – Prof. Masahiro Tsuji (ALD)

• Univers of Tokyo – Prof. Beate Heissig (HSC)

• University of Bergen

– Prof. Kamal Mustafa (Bone, MSC, Scaffolds, Bioprinting)

– Prof. Lars Bø (MS, CI)

– Prof. Kjell-Morten Myhr (MS, CI)

– Prof. Emmet Mc Cormark (HSC, imaging)

• Student mobility and exchange (PhD and postdoc)

• Common publications

• Include and Technology Transfer Offices and Industry

• Joint grant applications

– Japan Agency for Medical Research and Development

(AMED)

– Research Council of Norway (RCN)

– Other funding agencies in Norway and Japan

– EU Commission

Thank you for your attention!