Workshop on Regenerative Medicine/Stem Cells

Transcription

1 Workshop on Regenerative Medicine/Stem Cells Kamal Mustafa, University of Bergen Yasuhiko Tabata, Kyoto University Round Table Meeting Health, care and welfare technology June 7 th, 2018, Tokyo, Japan

2 Stem Cells in Clinical trials June registered studies stem cells US National Institutes of Health Bone marrow Mesenchymal stem cells Adipose stem cells 52 - Dental stem cells 49 Embryonic stem cells

3 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

4 Multiple sclerosis (MS) Disease severity and cost Inflammatory disease of the CNS Genetic and environmental risk factors MS-attack: % 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

5 Properties of MSCs and bone marrow derived cells Angiogenesis Suppression of inflammation, immune modulation Neuroprotection Cell fusion

6 MSC transplantation in MS Feasibility and safety Autologous culture-expanded BM MSCs Bonab et al. 2007,2012 (IT) Cohen et al (IV) Connick et al (IV) Karrussis et al (IT+IV in five) Llufriu et al (IV) Odinak et al (IV) Yamout et al (IT)

7 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

8 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?

9 Autogenous bone grafts Gold standard treatment 2 nd 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"

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11 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

12 UiB; Faculty of Medicine is the sponsor for 2 multicentre trials Regenerating bone defects using MSC and biomaterial as a new approach Cecilie Gjerde

13 Cast of alveolar ridge before and after augmentation illustrating the amount of bone reconstructed Bone biopsies Pre-augmentation 6 month after augmentation 13

14 First clinical trial and among few trials in Europe 14 uib.no

15 The results are very good! In spite of very limited blood supply because of area (posterior mandibula) and the membrane Patient

16 2 nd Trial involving reconstructing of: Cleft palate

17 With great expectations for the future of stem cells Increase number of patients (200) Phase II/III clinical trial Bergen Research Foundation (BFS) uib.no

18 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 /278/REK vest: Reparasjon av beindefekter i lange rørknokler ved bruk av stamceller uib.no

19 Conditioned Medium (CM) CM contain a lot of growth factors! Prof. Minoru Ueda, Nagoya University, Japan

20 Recovery of hind limbs Control SHED-CM

21 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

22 2 years after CI (60 F) Before Treatment

23 2 years after CI ( 60 F ) Before treatment

24 4 weeks 60 F CI

25 4 weeks 60 F CI

26 Scaffolds Temporary structural support Cellular microenvironment High surface area Facilitate cell migration Extracellular matrix secretion Release control of molecules and growth factors

27 Preparation of mechanically reinforced scaffold Prof. Yasuhiko Tabata It is important in cell-based regenerative therapy for efficient proliferation of stem cells Cell culture shrinkage collagen sponge A representative 3Dscaffold compatible to cells drawback shrinkage Sponge shrinkage during cell culture because of poor mechanical strength of sponge Cell culture collagen sponge reinforced The collagen sponge reinforced by PLLA fibers and beta-tcp granules Non-shrinkage scaffold

28 The in situ migration of neural cells in brain was enhanced by the local release of HGF, Nakaguchi et al Bone regeneration by dual release of SDF-1 and BMP-2 in the defects, Biomaterials 32 (2011)

29 Department of Clinical Dentistry Develop an innovative, biodegradable hydrogel bio-ink to fit the requirements of the 3-D printing technology 29 uib.no

30 Large collaborative projects between Norway-Japan Oral/maxillofacial bone preclinical/clinical Long bone preclinical/clinical Scaffold (matrix) production, characterization, functionalization with MSC, CM, GF - Preclinical studies - Clinical Trials 1. MS 2. ALD 3. CI (chronic) Transnasal delivery

31 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 )

32 (%) Survival % Survival Project Proposal: Screening and pre-clinical testing of new drugs to treat MDS/AML (Collaboration between Kitamura/Goyama Lab and Mc Cormack lab) Kitamura/Goyama lab Initial screening to identify candidate drugs for MDS and AML using murine models of MDS/AML Examples of candidate drugs Control Drug A Control Drug B p< (days) p= (days) Mc Cormack lab Confirmation of the effect of the candidate drugs using PDX models of MDS/AML

33 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)

34 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

35 Thank you for your attention!