michael k. racke, m.d. department of neurology · exogenous repair mechanisms in multiple sclerosis...

Exogenous Repair Mechanisms in Multiple Sclerosis

Michael K. Racke, M.D.Department of Neurology

Relevant Disclosures

Editorial Boards for Journal of Neuroimmunology (Editor-in-Chief), JAMA Neurology, and Annals of Neurology

Grant support from National Multiple Sclerosis Society and National Institutes of Health

Consultant for Abbvie, Genentech/Roche, EMD Serono, Novartis, TG Therapeutics, and Teva Neuroscience

Learning Objectives

Evaluate the key steps in the formation of the MS lesion and discuss how this relates to MS therapies

Identify possible mechanisms to help repair CNS in MS

Cell-based therapies for MS

Stem Cell Tourism

MS Genetics

• No detectable effect of shared environment on MS susceptibility in non-biological relatives such as spouse

• High disease concordance in monozygotic (25-30%) compared to dizygotic twins (3-5%)

Genome Wide Association Screens

• IMSGC (2007) Examined 931 family trios and 334,923 SNPs

• Identified HLA, IL-2R, IL-7R, CLEC16, CD58, EV15, TYK2

• Many genes are in the T helper cell differentiation pathway including

• TNFRSF1, IRF8, EOMES, IL12B, VCAM1, CD86, IL22RA2, CXCR5

MS Genetic Risk

• Outside the MHC, at least 100 genomic regions contribute to MS susceptibility

• Immunologically related genes seem to be those that confer susceptibility risk

How do current MS treatments work?

Most try to interrupt some step in disease pathogenesis

Multiple Sclerosis

Frohman, Racke, and Raine 2006

Experimental Autoimmune

Encephalomyelitis

Clinical Score Evaluation in EAE

1=limp tail

2=moderate hind limb weakness

3=severe hind limb weakness

4=hind limb paralysis

5=hind and fore limb paralysis

6=death due to EAE

Multiple Sclerosis

Frohman, Racke, and Raine 2006

0 5 10 15 20 25 30 35 40 45 500

1

2

3

4 siRNA-NS (n=7)siRNA-NogoA (n=8)

Days Post Transfer

Mea

n C

linic

al S

core

0 5 10 15 20 25 30 35 40 450

1

2

3

4 siRNA-NS (n=11)siRNA-NogoA (n=11)

Days Post Immunization

Mea

n C

linic

al S

core

siRNA-NS siRNA-NogoA0

1000

2000

3000

4000

5000 No AntigenMOG35-55

IFN

[pg

/ml]


100

200

300

400

500 No AntigenMOG35-55

IL-1

7 [p

g/m

l]


2000

4000

6000

8000

10000No AntigenMOG35-55

CP

M

A B

C D E

Reprinted with permission from Yang et al. Ann Neurol 2010

Yang et al. Annals of Neurology 2010

NogoA Expression in EAE Lesion

Bor

der

Lesi

on

Bor

der

L

esio

n

siRNA NS

siRNA NogoA


Neurite Sprouting In EAE

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Day

41

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-D

ay 1

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siR

NA

-Nog

oA

siR

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-NS

siR

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oA

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-NS


Attempt to Promote Remyelination

Regulation of Experimental Autoimmune Encephalomyelitis with Insulin-like Growth Factor (IGF-1) and IGF-1/IGF–binding Protein-3 Complex (IGF-1/IGFBP3)

Amy E. Lovett-Racke, Patrice Bittner, Anne H. Cross, Joseph A. Carlino, and Michael K. RackeDepartment of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110

J. Clin. Invest.1998. 101:1797–1804.

IGF-1 bound to IGF1BP3 Made EAE Worse

My first paper in 1991

TGF-beta for SPMS failed

miRNAs in MS target TGF- signaling

TGFβ

TGFβR1

Smad2P

Smad binding domains

Smad4

Smad2

TGFβR2

Smad2P

Smad4

Smad2P

Smad7

Cytoplasm

Nucleus

miR-let-7miR-18miR-27miR-128miR-340

miR-27miR-128miR-340miR-545miR-573

miR-21miR-33miR-181miR-519

miR-let-7 miR-27miR-128 miR-545miR-573 miR-642

miR-340miR-573

TGFβ

TGFβR1

Smad2P

Smad2PP

Smad binding domains

Smad4Smad4

Smad2Smad2

TGFβR2

Smad2P

Smad2PP

Smad4Smad4

Smad2P

Smad2PP

Smad7

Cytoplasm

Nucleus

miR-let-7miR-18miR-27miR-128miR-340

miR-27miR-128miR-340miR-545miR-573

miR-21miR-33miR-181miR-519

miR-let-7 miR-27miR-128 miR-545miR-573 miR-642

miR-340miR-573

Severin et al. Brain 2016

INTERNATIONAL CONFERENCE ON CELL-BASED THERAPIES FOR MULTIPLE SCLEROSIS

Nov 19-21, 2015Lisbon, Portugal

Organized under the auspices of the International Advisory Committee on Clinical Trials in Multiple Sclerosis

Cell-based therapies for MS

Cell types• Embryonic stem cells

• Adult stem cells of hematopoetic origin-R.Nash/J. Bowen, R. Saccardi, P. Muraro

• Oligodendrocyte precursor cells-A. Goodman

• Mesenchymal stromal (stem) cells-

M. Freedman

Potential Therapeutic Targets for Stem Cells in Multiple Sclerosis

Reduce inflammation Protect from demyelinationand axonal transection

Cell replacement oraugment intrinsic

repair mechanisms

Goodman. ACTRIMS. 2016.

Embryonic Stem Cells

• Source– Inner cell mass of blastocyst-stage

embryos

• Advantages– Indefinite self-renewal capacity

– Pluripotency – ability to generate all tissues

• Disadvantages– Practical and ethical issues

– POTENTIAL for teratoma, neuroepithelial tumors, and heterotopia formation


Oligodendrocyte Precursor Cells

• Source– Multipotent cells derived from

embryonic, fetal, neonatal, or adult CNS

• Advantages– Culture conditions can be

manipulated to promote proliferation or differentiation into neurons, astrocytes, or oligodendrocytes

• Disadvantages– Practical and ethical issues– Limited proliferation capacity– Require direct injection– Require immunosuppression


Goldman et al. Science. 2012.

Mesenchymal Stem Cells

• Source– Stromal cells that can be isolated

from many adult tissues

• Advantages– Adult source tissues– Can be cultured to purity in high

numbers– Immunomodulatory, protective, and

reparative properties– Immuno-privileged– Can be administered locally or

peripherally

• Disadvantages– Finite proliferative capacity


Mesenchymal stromal (stem) cells (MSC) showed therapeutic benefits in an animal model of idiopathic Parkinson disease1…

1Park et al. J.NeuroChem. 2008.www.parkinsons-tmj.org

…a disease with a known anatomical lesion and a relatively well-understood pathogenesis

Immune Ablation and Reconstitution“Rebooting the Immune System”

• Rationale – eliminate autoreactive immune cells and replace with a new immune system

• Immunoablation– High-dose cytotoxic agents

– Alemtuzumab

– Total body irradiation

• Reconstitution– Spontaneous

– Hematopoietic stem cell transplantation – bone marrow or blood, autologous or allogeneic


Immunoablation and Autologous HSCT

Study Design Results Comments

ASTIMS 1 • RR/SP MS with worsening EDSS and Gd+ on therapy

• Randomized to HDIT/AHSCT (n=9) vs Mitox (n=12)

• 4-yr follow-up

Benefit on:• New T2 lesions

(RR 0.21 p=0.00016)

• GdE lesions• Relapses

• Slow accrual• Small sample size• Mitox no longer used

HALT-MS 2 • RR MS with >2 relapses and worsening EDSS on therapy

• Single arm HDIT/AHSCT (n=24)

• 3 of 5-yr follow-up

• Event-free survival 78.4% (MRI, relapse, EDSS)

• Small sample size• Uncontrolled

NWU case series 3

• RR (n=123) or SP (n=28) MS• Nonmyeloablative AHSCT• Median follow-up of 2 yr

(n=145), up to 5 yr

• Median EDSS (4.0 to 3.0)

• 50% had >1.0-point improvementat 2 yr

• Large sample size• Better tolerability• Expectation, relapse

recovery or resolution of activity may explain improved EDSS

1 Mancardi GL et al. Neurology 2015; 84:981-988.2 Nash RA et al. JAMA Neurol 2015; 72:159-169.3 Burt RK et al. JAMA 2015; 313:275-284.

https://www.niaid.nih.gov/about/Pages/2015.aspx

HALT MS

• Autologous stem cell transplants for patients with highly active multiple sclerosis

• High-Dose Immunosuppressive Therapy and AutologousHematopoietic Stem Cell Transplantation for Relapsing-Remitting Multiple Sclerosis (HALT-MS) A 3 Year InterimReport

JAMA Neurology 72 (2):159-169, February, 2015

No Evidence of Disease Activity(NEDA)

• No clinical progression (EDSS)

• No clinical relapse

• No MRI activity

Disease Activity in HALT MS Patients

%NEDA in various MS trials

Trial Years Placebo Agent

AFFIRM 1 15 47

AFFIRM 2 7 37

CLARITY 2 16 46

FREEDOMS 2 13 33

DEFINE 2 15 28

HALT MS 3 NA 78

Rising DMT Cost

Drug US Approval Annual Cost at Approval

2013 Cost Annualized change

IFN-beta-1b B 7/23/93 $11,532 $61,529 21.0

IFN-beta-1a IM

5/17/96 $8,723 $62,394 34.6

GA 12/20/96 $8,292 $59,158 35.7

IFN-beta-1a SC

3/7/02 $15,262 $66,394 28.1

Natalizumab 11/23/04 $25,850 $64,233 16.2

IFN-beta-1b G 8/14/09 $32,826 $51,427 13.0

Fingolimod 9/21/10 $50,775 $63,806 7.9

Teriflunomide 9/12/12 $47,651 $57,553 16.8

DMF 3/27/13 $57,816 $63,315 13.8

Hartung et al., Neurology 2015; 84: 2185-92.

Stem Cell Tourism

Special CommunicationResponsibilities of Health Care Professionalsin Counseling and Educating Patients With Incurable Neurological Diseases Regarding “Stem Cell Tourism” Caveat Emptor

Michelle Bowman, MD; Michael Racke, MD; John Kissel, MD; Jaime Imitola, MD

JAMA Neurology Published online August 31, 2015

Resource “ The iPS cells Phenogenetic map project”:iPhemap iPhemap: An atlas of phenotype to genotype relationships of human induced pluripotent stem cell models of neurological diseases.www.iphemap.org Abstract no.

Resource “ The iPS cells Phenogenetic map project”:iPhemap

iPhemap: An atlas of phenotype to genotype relationships of human induced pluripotent stem cell models of neurological diseases.

Meta-analysis of iPS phenotypes

Conclusions

Must understand context in which exogenous treatment is usedOf cell based therapies, autologous stem cell transplantation most ready for prime timeAHSCT is both highly effective and in today’s therapeutic climate, may even be cost effective

Acknowledgements

michael k. racke, m.d. department of neurology · exogenous repair mechanisms in multiple sclerosis...

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