advances in stem cell therapies in the treatment of ms

North Bristol NHSNHS Trust

University of BRISTOL

BNI

Institute of Clinical Neurosciences

Advances in stem cell therapies in the treatment of MS MS Trust, Windsor, November 2015Neil Scolding

oligodendrocyteprecursors

astrocytesbrain stem cell

stem cells



stem cells

1

neurones

skin

heart

kidney

22

stem cells



cell replacement

Bunge et al 1961

Carswell 1838

embryonic oligodendrocytesadult oligodendrocytes Schwann cellsolfactory gliaxenotransplants?stem cells


?

Scolding, Franklin et alBrain 1998

NG2 Wilson/ Raine/ScoldingJ Neuroimmunol 2006

oligodendrocyte progenitors are not rare

in MS lesions - Wolswijk, Trapp, Dowling, Reynolds

Hoechst Nestin 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



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.

Charcot 1872 Carswell 1838


North Bristol NHS

NHS Trust


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acute relapseacute relapse


North Bristol NHS

NHS Trust


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progressionprogressionacute relapseacute relapse


North Bristol NHS

NHS Trust


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axon lossaxon lossneuron lossneuron loss

• Not so cell specific• Not so site specific• No single pathological process



oligodendrocyte replacement

?




?

‘restorative’ cell therapy




cell replacement- immune system


small molecules for myelin repair

– anti-lingo antibodies– ‘re-positioned’ drugs

• miconazole, clobetasol• bexarotene (retinoid X-

receptor gamma agonist)




cell replacement- immune system


small molecule therapy for myelin repair


North Bristol NHS

NHS Trust


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HSCT

HSCT

haematopoetic stem cell

conditioning e.g., carmustine,

cytarabine, etoposide, melphalan,

alemtuzumab

graftingus. autologous

HSCT




alemtuzumab


harvesting

HSCT




alemtuzumab


harvesting/inductioncyclophosphamide

GCSF

HSCT




alemtuzumab



GCSF

HSCT

HSCT•80-85% reduced relapses•mortality 1.3%-5%•??effect on progression




alemtuzumab



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)




haematopoeitic stem cell therapy

HSCT



HSCT

HSCT

adapted from: Korbling & Estrov, NEJM 2003Adult 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

Bone marrow stem cells 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


North Bristol NHS

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Intravenous injection of MSCs ameliorates EAE

Pluchino et al. Nature 2005 436: 266-71Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism.


North Bristol NHS

NHS Trust


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BNI


I. NEUTROPHIL MOLECULES AND FUNCTIONSI.A. ADHESION AND MIGRATIONI.A.1. Traffic and marginationI.A.2. Adhesion to the Endothelial WallRolling and TetheringNeutrophil Priming During RollingFirm Adhesion and SpreadingI.A.3 Extravasation and Diapedesis Toward InflammatoryStimuliTransendothelial MigrationMigration Within Interstitial TissuesSignaling by ChemoattractantsTransepithelial MigrationI.B. PHAGOCYTOSIS, DEGRANULATION ANDBACTERIA KILLINGI.B.1. PhagocytosisI.B.2. DegranulationGranule BiogenesisMechanisms of DegranulationI.B.3. Microbicidal MoleculesNADPH-Derived OxidantsThe H2O2-Myeloperoxidase SystemNitric Oxide-Synthase-Derived Reactive NitrogenIntermediatesGranule ProteinsAntimicrobial ProteinsProteasesI.C. CYTOKINE SYNTHESISI.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 ChemokinesI.C.4. Modulation of Cytokine Expression by NeutrophilsIFN-gIL-10IL-4 and IL-13I.C.5. Molecular Regulation of Cytokine ProductionI.D. APOPTOSIS AND RESOLUTION OF ACUTEINFLAMMATIONI.D.1. Progressive Decrease of Neutrophil RecruitmentI.D.2. Apoptosis in Resolution of InflammationII. NEUTROPHILS IN PATHOLOGYII.A. Bacterial InfectionII.B. Tissue Injury-Induced Inflammation: Ischemia-Reperfusion InjuryII.C. Crystal-Induced InflammationII.D. Complement-Induced Inflammation and OxidativeStress: HemodialysisII.E. Immune Complex-Induced Inflammation:Antibody-Mediated GlomerunephritisII.F. Cytokine-Induced Inflammation: RheumatoidArthritisII.G. Antineutrophil Cytoplasmic Antibodies andVasculitis: Autoimmunity Against NeutrophilComponentsII.H. Genetic Disorders of Neutrophil Regulations:Hereditary Periodic Fever SyndromesII.I. Cystic Fibrosis: The Paradox of an Exacerbationof Neutrophil-Mediated Tissue Damageand a Concomitant Persistence of Infection

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

adapted from: Korbling & Estrov, NEJM 2003

bone marrow cells

Study of Intravenous Autologous 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

Institute of Clinical NeurosciencesStudy of Intravenous Autologous Marrow in

Multiple Sclerosis

SIAMMS – results, electrophysiology

Global EP Scores at 1 yr BM CT patients all improve p=0.02


Intervention:

day case procedure

BM harvest (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

Cell therapy trials in MS

Rice, Kemp, Wilkins & Scolding Lancet 2013

18 clinical studies reported or known to be in progress

MSCsUnselected marrowUmbilical cord cellsAdipose cells

Importance of regulated clinical trials



Bristol Institute of Clinical Neurosciences

Cell therapy trials in MS

Rice, Kemp, Wilkins & Scolding Lancet 2013

47 clinical studies reported or known to be in progress



Bristol Institute of Clinical Neurosciences




haematopoeitic stem cell therapy

HSCT



PHASE I,II

PHASE IIPHASE I

Department of Neurology, University of Texas Medical School at Houston, Texas, USA

The Silverman

Family TrustMS TrustAtaxia UK

MRC

Rosetrees Trust

Multiple Sclerosis Society

Sir Halley Stewart

Trust

Friends of Frenchay

NIHR

North Bristol NHS Trsut Research

Foundation

advances in stem cell therapies in the treatment of ms

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