Stem Cell Therapy: Miracle Cure or Mirage?

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1 Stem Cell Therapy: Miracle Cure or Mirage? Nipan Israsena M.D., Ph.D. Head, Stem Cell and Cell Therapy Research Unit Faculty of Medicine, Chulalongkorn University Bangkok Thailand

2 BM transplantation 1950s HSC give rise to all the other blood cells Unlimited self-renewal Figure Molecular Biology of the Cell ( Garland Science 2008)

3 The discoveries of other somatic (adult) stem cells

4 Stem cells Somatic (Adult) stem cells Hematopoietic stem cells BM, cord blood Epithelial stem cells skin, cornea Mesenchymal stem cells Endothelial stem cells Neural stem cells Other tissue specific stem cells cardiac, gut, breast

5 Epithelial stem cells In 1984, Howard Green and his colleagues reported that the life of two children presenting fullthickness burns covering over 95% of their body surface was saved by transplantation of autologous cultured keratinocytes Permanent epidermal regeneration, confirmed by followup studies over 20 year period, has been achieved in many of these patients

6 Stem Cells of the Corneal Epithelium The corneal epithelium is a squamous epithelium that is constantly renewing, with a vertical turnover of 7 to 14 days Limbal stem cell deficiency corneal vascularization, poor epithelial integrity, conjuctivalization

7 NEJM 2000

8 Relation between Clinical Results and Percentage of p63-bright Cells in Limbal Stem-Cell Cultures. The clinical results were successful at up to 10 years (at a median of 2 years) in more than 75% of the patients treated. June 2010

9 Limitation Adult stem cells are only able to manufacture cell varieties within their own lineage. Not every tissues has stem cells eg pancreas, adult kidney Ex vivo cultivation is limited eg HSC Some type of SC are difficult to obtain eg brain Transplantaion methods + engraftment difficult for solid tissue - bone, CNS

10 Cells integration and survival after injection are still limited Bone

11 Last 15 Years

12 Pluripotent Stem Cells and Cell Reprogramming John Gurdon Nuclear transfer Ian Wilmut Cloned Dolly Jame Thomson Derived human ES cells Shinya Yamanaka Mouse ips cells SY and JT reported human ips cells JG and SY Receive Nobel Prize

13 Human Pluripotent Stem Cells Capable to differentiate into the three somatic germ layers - all cell types of human body Have the unlimited capacity to self renew Invaluable resource of cells for various clinical applications

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15 2 patients one with dry age-related macular degeneration and one with Stargardt s disease The hesc-derived RPE cells showed no signs of hyperproliferation, tumorigenicity, ectopic tissue formation, or apparent rejection after 4 months. Lancet 2012

16 Pluripotent stem cell can be generated from patient s own somatic cells eg. skin, blood Autologous cell therapy Disease modeling Takahashi and Yamanaka, Cell 126, 2006

17 Masayo Takahashi MD. Ph.D.

18 Pluripotent stem cell research is very promising but will need at least a few more years before it can be applied to routine clinical practice What s about somatic stem cells? Can we use them for broader clinical applications?

19 10-15 years ago there was a popular concept of adult stem cell plasticity

20 Evidence of adult stem cell plasticity BMDC Mouse BM cells could give rise to skeletal muscle cells when transplanted into a mouse muscle that had been damaged by an injection of a muscle toxin (Science 1998) Transplanted BM cells could produce hepatocytes (Science 1999) Bone marrow stem cell -> brain (Science 2000) Endothelial ( J Clin Invest 2000) myocardial cells (Nature 2001)

21 Bone marrow cells and myocardial regeneration. a, Myocardial infarct (MI) injected with Lin- c-kitpos cells from bone marrow (arrows). Arrowheads indicate regenerating myocardium; VM, viable myocardium. Orlic et al Nature 2001

22 Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts When both cardiomyocyte restricted and ubiquitously expressed reporter transgenes were used to track the fate of haematopoietic stem cells after 145 transplants into normal and injured adult mouse hearts. No transdifferentiation into cardiomyocytes was detectable when using these genetic techniques to follow cell fate, and stemcell-engrafted hearts showed no overt increase in cardiomyocytes compared to sham-engrafted hearts. Murry et al., Nature 2004

23 Technical problems in identifying transplanted cells Failures to reproduce results Spontaneous cell fusion Unreliable markers Very rare event

24 Prof. Irving Weissman Stanford University No evidence of BM cells and cord blood transdifferentiation into neuron, cardiac muscle or other cell types Annual meeting The Royal College of Physician of Thailand 25 April 2013

25 Adult stem cell plasticity, even if it really exists, would be unlikely to generate sufficient number of cells to be clinically meaningful

26 Other Potential Benefits of Adult Stem cells Anti-inflamatory, immunomodulation secrete growth factors Promote angiogenesis Stimulate endogenous stem cells proliferation, tissue repair Early clinical trials - +/- Need more research before it can be used successfully in standard practice

27 Heart AHA Stem cell therapy to repair damaged hearts is in its infancy 2 of 5 clinical trials reported show some positive results (using cardiac stem cells) Questions still need to be addressed Type of stem cell Cell preparation Delivery system Timing of delivery Autologous or allogenic

28 Stem cell product approvals world-wide Three products in South Korea (allogeneic for AMI, anal fistula; autologous for knee cartilage repair) Prochymal approved in CA, NZ (allogeneic MSC for GVHD) Three cord blood (hematopoietic progenitor cell) products approved by FDA

29 Controversial Stem Cell Business Clinics that use stem cell in aesthetic procedures Clinic that offer stem cell treatment for chronic untreatable diseases IHD, stroke, Alzheimer s, Spinal cord injury, chronic kidney disease, etc - unproven therapy Private cord blood bank

30 Advertising claims or clinical practice using stem cellls no scientific evidence

31 Risks of cell-based therapy Can not be sterilized Culture increase risk of contamination, genetic mutation Immunogenicity autologous vs allogeneic Can be long-term persistence- long-term effect: good or bad Hetergenousity Secrete various proteins Properties of cells may change after transplantation

32 Pathology of masses in severe EAE following ICV transplantation of BMSCs Grigoriadis et al., Experimental Neurology 2011

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34 Four years after the first treatment he was diagnosed with a multifocal brain tumor. The biopsied tumor was diagnosed as a glioneuronal neoplasm.

35 Hundreds of poorly regulated clinics that offer unproven stem-cell therapies now running world-wide

36 In 2006, patient elected to undergo stem cell therapy for treatment of renal disease at a private clinic. For this treatment, autologous HSCs were mobilized by G-CSF and collected from peripheral blood. The stem cell preparation was later injected percutaneously into the regions of both kidneys via multiple blind passes during a single procedure. Journal of the American Society of Nephrology 2010

37 Europe's largest stem cell clinic, which is at the centre of a scandal over the death of a baby given an injection into the brain, has been shut down The child, who was from Romania, was injected in the brain with stem cells but suffered internal bleeding. Three months earlier, a boy aged 10 from Azerbaijan had almost died when the same procedure went wrong. The doctor who carried out the operation remains under criminal investigation.

38 Florida Medical Board vs Zannos Grekos Zannos Grekos, MS formerly escorted patients to DR for auto BM transplants for heart Received emergency restriction after US patient died following BM injection into carotid artery License suspended after second patient died during surgical preparation for an adipose-derived MSC auto-transplant for a lung condition

39 Complications Ectopic tissues esp. heterologous usage Promote tumor formation/ metastasis Allergy Contamination - virus Vessel occlusions stoke, MI, pulmonary embolism Systemic effects Death

40 Thai Medical Council(TMC) Regulation At present only HSC transplantation for hematopoietic diseases is considered a standard stem cell therapy in Thailand For use of stem cells other than above Treatments: need TMC approval (documentations required) Research: requires institutional EC/IRB and TMC stem cell committee approval Practitioners require TMC certification and approval

41 Advertisements usually found at private cord blood bank -1. For the benefit of your children -2. Stem cells have the ability to develop into any of the 220 cell types that make up the human body -3. Can be used in > 100 diseases -.. But It is only a half-truth Need monitoring

42 THANK YOU FOR YOUR ATTENTION