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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!