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Advances in stem cell therapies in the treatment of MS
This document summarizes advances in stem cell therapies for the treatment of multiple sclerosis (MS). It discusses several approaches: 1) Transplantation of oligodendrocyte precursor cells, which may not be effective due to the presence of endogenous precursors in MS lesions. 2) Hematopoietic stem cell transplantation, which reduces relapses in 80-85% of cases but has no proven effect on progression and risks of 1.3-5% mortality. 3) Mesenchymal stem cells and bone marrow mononuclear cells, which may aid repair through immunomodulation and other mechanisms rather than direct cell replacement.
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Advances in stem cell therapies in the treatment of MS
- 1. North Bristol NHS NHSTrust University of BRISTOL BNI Institute of Clinical Neurosciences Advances in stem cell therapies in the treatment of MS MS Trust, Windsor, November 2015 Neil Scolding
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- 6. Bunge et al1961
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- 13. Scolding, Franklin etal Brain 1998 NG2 Wilson/ Raine/Scolding J Neuroimmunol 2006 oligodendrocyte progenitors are not rare in MS lesions - Wolswijk, Trapp, Dowling, Reynolds
- 14. Hoechst Nestin Musashi-1 HoechstNestin Musashi-1 BRISTOL Institute of Clinical Neurosciences Nestin –PDGFαR Nestin-GFAP Nestin-doublecortin Nestin Hoechst Ki67 Nestin Ki67 Hoechst Endogenous neural precursors respond to disease processes in MS Snethen, Love & Scolding Regen Med. 2008 3: 835-47. Nestin-doublecortin Hoechst Nestin NG2
- 15. Hoechst Nestin Musashi-1 HoechstNestin Musashi-1 BRISTOL Institute of Clinical Neurosciences Nestin –PDGFαR Nestin-GFAP Nestin-doublecortin Nestin Hoechst Ki67 Nestin Ki67 Hoechst Nestin-doublecortin Hoechst Nestin NG2 .......These findings are important to an understanding of the remyelination of lesions of multiple sclerosis and imply that transplantation of oligodendrocyte precursor cells will probably not be an effective therapy for multiple sclerosis.
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- 17. Institute of ClinicalNeurosciences North Bristol NHS NHS Trust University of BRISTOL ccssnnbb BNI acute relapseacute relapse
- 18. Institute of ClinicalNeurosciences North Bristol NHS NHS Trust University of BRISTOL ccssnnbb BNI progressionprogressionacute relapseacute relapse
- 19. Institute of ClinicalNeurosciences North Bristol NHS NHS Trust University of BRISTOL ccssnnbb BNI progressionprogressionacute relapseacute relapse axon lossaxon loss neuron lossneuron loss
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- 23. Not so cellspecific Not so site specific No single pathological process
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- 26. oligodendrocyte precursors astrocytes brain stem cell oligodendrocyte replacement cell replacement -immune system ‘restorative’ cell therapy
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- 29. small molecules formyelin repair – anti-lingo antibodies – ‘re-positioned’ drugs • miconazole, clobetasol • bexarotene (retinoid X-receptor gamma agonist)
- 30. oligodendrocyte precursors astrocytes brain stem cell oligodendrocyte replacement cell replacement -immune system ‘restorative’ cell therapy small molecule therapy for myelin repair
- 31. Institute of ClinicalNeurosciences North Bristol NHS NHS Trust University of BRISTOL ccssnnbb BNI progressionprogressionacute relapseacute relapse axon lossaxon loss neuron lossneuron loss
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- 33. haematopoetic stem cell conditioning e.g., carmustine, cytarabine,etoposide, melphalan, alemtuzumab grafting us. autologous HSCT
- 34. haematopoetic stem cell conditioning e.g., carmustine, cytarabine,etoposide, melphalan, alemtuzumab grafting us. autologous harvesting HSCT
- 35. haematopoetic stem cell conditioning e.g., carmustine, cytarabine,etoposide, melphalan, alemtuzumab grafting us. autologous harvesting/induction cyclophosphamide GCSF HSCT
- 36. haematopoetic stem cell conditioning e.g., carmustine, cytarabine,etoposide, melphalan, alemtuzumab grafting us. autologous harvesting/induction cyclophosphamide GCSF HSCT HSCT •80-85% reduced relapses •mortality 1.3%-5% •??effect on progression
- 37. haematopoetic stem cell conditioning e.g., carmustine, cytarabine,etoposide, melphalan, alemtuzumab grafting us. autologous harvesting/induction cyclophosphamide GCSF HSCT “autologous HSCT does not appear to be effective against established progressive forms of MS …. additional trials of these protocols are probably not indicated for patients with progressive MS” (Hauser, 2015)
- 38. oligodendrocyte precursors astrocytes brain stem cell oligodendrocyte replacement haematopoeitic stem celltherapy HSCT ‘restorative’ cell therapy small molecule therapy for myelin repair
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- 40. adapted from: Korbling& Estrov, NEJM 2003 Adult stem cells for tissue repair - a new therapeutic concept Bone marrow stem cells Circulating bone marrow stem cells enter the brain and spinal cord and may contribute to the repair of damaged tissue
- 41. Bone marrow stemcells stimulate or re-programme repair both directly and through a range of ‘non-canonical’ mechanisms :- • fusion • immune modulation • neuroprotection • growth factor production • reduced scar formation • new vessel formation • REGULATE LOCAL TISSUE STEM CELLS • transdifferentiation Blau, H. M. Cell fusion: A twist of fate. Nature 419, 437 (2002). Rice CM, Scolding NJ. Adult stem cells--reprogramming neurological repair? Lancet. 2004; 364:193-199
- 42. Institute of ClinicalNeurosciences North Bristol NHS NHS Trust University of BRISTOL ccssnnbb BNI progressionprogressionacute relapseacute relapse axon lossaxon loss neuron lossneuron loss
- 43. Intravenous injection ofMSCs ameliorates EAE Pluchino et al. Nature 2005 436: 266-71 Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism.
- 44. Institute of ClinicalNeurosciences North Bristol NHS NHS Trust University of BRISTOL ccssnnbb BNI progressionprogressionacute relapseacute relapse axon lossaxon loss neuron lossneuron loss
- 46. Institute of ClinicalNeurosciences North Bristol NHS NHS Trust University of BRISTOL ccssnnbb BNI progressionprogressionacute relapseacute relapse axon lossaxon loss neuron lossneuron loss
- 47. J. Neurosci. Res.Vol.84, pp 587-595 Copyright © 2006 Wiley-Liss, Inc., A Wiley Company Luxol fast blue and Bielshowsky silver axon densityaxon density
- 49. North Bristol NHS NHSTrust University of BRISTOL BNI Institute of Clinical Neurosciences
- 51. I. NEUTROPHIL MOLECULESAND FUNCTIONS I.A. ADHESION AND MIGRATION I.A.1. Traffic and margination I.A.2. Adhesion to the Endothelial Wall Rolling and Tethering Neutrophil Priming During Rolling Firm Adhesion and Spreading I.A.3 Extravasation and Diapedesis Toward Inflammatory Stimuli Transendothelial Migration Migration Within Interstitial Tissues Signaling by Chemoattractants Transepithelial Migration I.B. PHAGOCYTOSIS, DEGRANULATION AND BACTERIA KILLING I.B.1. Phagocytosis I.B.2. Degranulation Granule Biogenesis Mechanisms of Degranulation I.B.3. Microbicidal Molecules NADPH-Derived Oxidants The H2O2-Myeloperoxidase System Nitric Oxide-Synthase-Derived Reactive Nitrogen Intermediates Granule Proteins Antimicrobial Proteins Proteases I.C. CYTOKINE SYNTHESIS I.C.1. TNF-a as a Proinflammatory Cytokine I.C.2. IL-1 and IL-1 Receptor Antagonist (IL-1-Ra) I.C.3. IL-8 as a Prototype of Chemokines I.C.4. Modulation of Cytokine Expression by Neutrophils IFN-g IL-10 IL-4 and IL-13 I.C.5. Molecular Regulation of Cytokine Production I.D. APOPTOSIS AND RESOLUTION OF ACUTE INFLAMMATION I.D.1. Progressive Decrease of Neutrophil Recruitment I.D.2. Apoptosis in Resolution of Inflammation II. NEUTROPHILS IN PATHOLOGY II.A. Bacterial Infection II.B. Tissue Injury-Induced Inflammation: Ischemia- Reperfusion Injury II.C. Crystal-Induced Inflammation II.D. Complement-Induced Inflammation and Oxidative Stress: Hemodialysis II.E. Immune Complex-Induced Inflammation: Antibody-Mediated Glomerunephritis II.F. Cytokine-Induced Inflammation: Rheumatoid Arthritis II.G. Antineutrophil Cytoplasmic Antibodies and Vasculitis: Autoimmunity Against Neutrophil Components II.H. Genetic Disorders of Neutrophil Regulations: Hereditary Periodic Fever Syndromes II.I. Cystic Fibrosis: The Paradox of an Exacerbation of Neutrophil-Mediated Tissue Damage and a Concomitant Persistence of Infection
- 52. adapted from: Korbling& Estrov, NEJM 2003 Circulating bone marrow stem cells enter the brain and spinal cord and may contribute to the repair of damaged tissue Bone marrow cells for tissue repair
- 53. adapted from: Korbling& Estrov, NEJM 2003 bone marrow cells
- 54. Study of IntravenousAutologous Marrow in Multiple Sclerosis (SIAMMS) 6 participants Mean age 48 yrs Disease duration 16 yrs Median EDSS 6 Intervention: Daycase procedure Bone marrow harvest (250-750ml) under general anaesthesia Bone marrow is filtered Intravenous infusion of autologous marrow cells No myelo- or lymphoablation Cell dose 9 x109 TNC
- 55. Institute of ClinicalNeurosciences Study of Intravenous Autologous Marrow in Multiple Sclerosis SIAMMS – results, electrophysiology Global EP Scores at 1 yr BM CT patients all improve p=0.02 Institute of Clinical Neurosciences
- 56. Intervention: day case procedure BMharvest (250-750ml), GA i/v infusion, ~1010 filtered cells no myelo-ablation delayed vs. immediate treatment with generous support from the Silverman Family Foundation Phase II Trial 80 patients Assessment of Bone Marrow Cell Therapy in Multiple Sclerosis ACTiMuS Institute of Clinical Neurosciences BRISTOL
- 59. Cell therapy trialsin MS Rice, Kemp, Wilkins & Scolding Lancet 2013 18 clinical studies reported or known to be in progress MSCs Unselected marrow Umbilical cord cells Adipose cells Importance of regulated clinical trials University of BRISTOL North Bristol NHS NHS Trust Bristol Institute of Clinical Neurosciences
- 60. Cell therapy trialsin MS Rice, Kemp, Wilkins & Scolding Lancet 2013 47 clinical studies reported or known to be in progress University of BRISTOL North Bristol NHS NHS Trust Bristol Institute of Clinical Neurosciences
- 61. oligodendrocyte precursors astrocytes brain stem cell oligodendrocyte replacement haematopoeitic stem celltherapy HSCT ‘restorative’ cell therapy small molecule therapy for myelin repair PHASE I,II PHASE II PHASE I
- 62. Department of Neurology,University of Texas Medical School at Houston, Texas, USA
- 63. The Silverman Family Trust MSTrust Ataxia UK MRC Rosetrees Trust Multiple Sclerosis Society Sir Halley Stewart Trust Friends of Frenchay NIHR North Bristol NHS Trsut Research Foundation
Editor's Notes
- #11 Remyelination = cell therapy
- #12 Remyelination = cell therapy
- #18 Repair not as good as prevention…but tried this for 50 years, etc; ‘repair’ synonymous with remyelination…?
- #19 Repair not as good as prevention…but tried this for 50 years, etc; ‘repair’ synonymous with remyelination…?
- #20 …but this hasn’t dramatically dampened enthusiasm for cell remyelinating therapies partly
- #22 ….doesn’t remove rationale altogether, overstated – but does illustrate complexity, and how a one-size-fits-all repair strategy is not sufficient for ms
- #23 Remyelination = cell therapy
- #28 Remyelination = cell therapy
- #29 Remyelination = cell therapy
- #30 Remyelination = cell therapy
- #32 …but this hasn’t dramatically dampened enthusiasm for cell remyelinating therapies partly
- #41 Actually physiological – evidence? – CAN isolate them from circulating blood; and lots of bmtx pm studies, eg….
- #43 …but this hasn’t dramatically dampened enthusiasm for cell remyelinating therapies partly
- #45 …but this hasn’t dramatically dampened enthusiasm for cell remyelinating therapies partly
- #47 …but this hasn’t dramatically dampened enthusiasm for cell remyelinating therapies partly
- #53 Actually physiological – evidence? – CAN isolate them from circulating blood; and lots of bmtx pm studies, eg….
- #54 Actually physiological – evidence? – CAN isolate them from circulating blood; and lots of bmtx pm studies, eg….