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Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME): pathogenesis, diagnostic biomarkers & clinical trials PowerPoint PPT Presentation


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Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME): pathogenesis, diagnostic biomarkers & clinical trials . Dr Jonathan R Kerr MD, PhD, FRCPath Sir Joseph Hotung Senior Lecturer in Inflammation St George’s University of London. Chronic Fatigue Syndrome (CFS). Epidemiology

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Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME): pathogenesis, diagnostic biomarkers & clinical trials

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Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME): pathogenesis, diagnostic biomarkers & clinical trials

Dr Jonathan R Kerr MD, PhD, FRCPath

Sir Joseph Hotung Senior Lecturer in Inflammation

St George’s University of London


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Chronic Fatigue Syndrome (CFS)

Epidemiology

Prevalence of 0.5%

More common in females (6:1)

Sudden onset

Preceding virus infection (‘flu-like illness, outbreaks, specific viruses)

Exposure to toxins, chemicals, pesticides, vaccination

Pre-existing emotional stress


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Chronic Fatigue Syndrome (CFS)

Studies of Pathogenesis

Immune system -IC’s, IgG, B cells, NK Th2 phenotypecytokine dysregulation / chronic immune activation

Infection - virus, bacterium

Nervous system -paresis, visual loss, ataxia, confusionabnormal metabolism of 5-HIAA, A-V, 5-HT, PRLbrain scan abnormalities

Endocrine system -slight HPA axis

Cardiovascular system - vasodilatation

Psychological function -depression & anxiety

Genetic predisposition -deduced from twin studies


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Active infections / insults in 200 CFS patients

Enterovirus109Chlamydia pneumoniae18Epstein-Barr virus6Recurrent VZV infection6Parvovirus B19 infection3Hepatitis C virus3Cytomegalovirus3Postvaccination (pn, MMR or flu)3Toxic mould exposure2Recurrent HHV-6 infection 1

Unknown44

Chia et al. Clin Infect Dis 2003;36:671-2.


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Chronic Fatigue Syndrome (CFS)

Treatment

Graded exercise therapy (GET)

Cognitive behavioural therapy (CBT)

Immunological – IVIG, interferon, terfenadine,

Pharmacological – hydrocortisone, NADH, DA agonist, MAOI, Vit B analog, galanthamine, fludrocortisone, antidep, SSRI, acyclovir, IFN inducer

Supplements – magnesium

Complementary / alternative – massage, osteopathy

Other – buddy/mentor program

specific treatment of virus infection


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Hypothesis for prolonged fatigue / CFS

Insults

A

B

C

D

E

F

G

H

I

J

K

Initial processes

Final common pathway(s)

CFS


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Overview of basic cell processes


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Microarray


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Microarray


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GENES

Taqman real-time PCR

Test gene

Control gene


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Pilot study

Study of Gene Expression in Chronic fatigue syndrome

Pilot study - 2005

Hypothesis: that abnormalities of gene regulation occur in CFS

25 CFS patients & 25 normal controls

Gene levels determined by Microarray analysis (9,522 genes) & real-time PCR


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Pilot study

16 CFS-associated Genes

ImmuneIL-10RAIL-10 receptor alphaCD2BP2 CD2 antigen binding protein 2

NeurologicalPRKCL1 Protein kinase C-like 1GABARAPL1 GABA(A) receptor associated protein like-1KHSRP KH-type splicing regulatory proteinNTE Neuropathy target esteraseGSN Gelsolin

MitochondrionMRPL23 Mitochondrial ribosomal protein L23EIF2B4 Euk. translation initiation factor 2B, subunit 4δ, tv-1EIF4G1Euk. Translation initiation factor 4G, subunit 1, tv-5

Apoptosis / cell cyclePDCD2 Programmed cell death 2, tv-1ANAPC11 Anaphase promoting complex subunit 11 homologBRMS1 Breast cancer metastasis suppressor 1

PeroxisomeABCD4 ATP-binding cassette subfamily D, member 4PEX16 Peroxisomal biogenesis factor 16

TranscriptionPOLR2G RNA polymerase II (DNA-directed) polypeptide G


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GENES


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Pilot study

Conclusion

A complex pathogenesis

Support for a biological process in CFS


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Hypothesis

A working model of CFS

T lymphocyte

Macrophage


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Hypothesis

A working model of CFS

T lymphocyte

Macrophage

cytokines, etc


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GENES

What are the human and virus gene signatures of CFS?

Phase 1-continued

Repeat microarray study

CFS patients and normal controls

Determine levels of ALL human and virus genes


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Phase-1 cont.

Phase-1 continued Study

Clinical aspects

1. Diagnosis according to CDC criteria

(Fukuda et al, 1994)

2. Assessment of health & associated symptoms:

CIDI

Cantab

McGill

Chalder

MOS-SF36

SPHERE

Pittsburgh


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GENES

Virus & Human genes in CFS

MPSSStudy

Microarraystudy

Microarray47,000 human genes27 CFS pts / 54 normalsEast Dorset CFS Service

MPSSALL genes sequenced20 CFS pts / 20 normalsUniversity of Cardiff


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GENES

MPSS

182

15

52

Microarray

Immune ResponseNeurological genesMitochondrial genesSelective Regulation


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Phase-1 cont.


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GENES


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GENES


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GENES

Human microRNAs in CFS


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GENES

Confirmation of specificity of CFS gene signature

Phase 2

Idiopathic CFS (n=500)

Infection-associated CFS (n=50)

Prolonged fatigue (n=50)

Normal fatigue (n=25)

Normals (n=100)

Rheumatoid arthritis (n=50)

Osteoarthritis (n=50)

Endogenous depression (n=50)


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GENES

Associations of CFS-associated genes with symptoms

Phase 3

CFS-associatedsymptoms

CFS-associatedgenes

Time (12 months)


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GENES

Virus genes in CFS

28 microbes

HerpesvirusesEnterovirusesParvovirusesCoxiella burnetiiMycoplasma pneumoniae Chlamydia pneumoniaeetc.etc.

MPSSStudy

Known virustriggers

28 microbes


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TREATMENTDEVELOPMENT

Clinical trials of treatment candidates

Phase 4

Human

Virus

NFKB

IL-6

Interferon-b

HIF1a

T cell activation

Acyclovir

Pleconoril

Clarithromycin

Interferon-b


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TREATMENTDEVELOPMENT

Clinical trials of treatment candidates

Phase 4

Human

Virus

NFKB

IL-6

HIF1a

T cell activation

Acyclovir

Pleconoril

Clarithromycin

Interferon-b


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Biomarkers

Development of a diagnostic test for CFS

SELDI-PC


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Biomarkers

SELDI-PC


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Biomarkers

Diagnostic test for CFS

**Collaboration with Dept of Paediatrics, Imperial College London


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Clinical Centres


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Acknowledgements

STUDY DESIGN & LABORATORY WORK

Deepika Devanur, St George’s University of London

Robert Petty, St George’s University of London

Beverley Burke, St George’s University of London

Narendra Kaushik, Imperial College London

Rob Wilkinson, Imperial College London

Clare McDermott, Dorset CFS Service

Jane Montgomery, Dorset CFS Service

David Fear, Kings College London

Tim Harrison, UCL

Paul Kellam, UCL

David AJ Tyrrell, CFS Research Foundation

Stephen T Holgate, University of Southampton

Emile Nuwaysir, Nimblegen Inc, USA.

Don Baldwin, University of Pennsylvania, USA

Peter Rogers, NBS

Diana Carr, NBS

Julie Williams, NBS

Frank Boulton, NBS

Andrew Bell, Poole Hospital

CLINICAL COLLABORATORS

Dr Selwyn Richards, Dorset CFS Service

Dr Janice Main, Imperial College London

Professor Terry Daymond, Sunderland

Professor Andrew Smith, University of Cardiff

Dr David Honeybourne, Birmingham

Dr Amolak Bansal, St Helier Hospital, Surrey

Professor Jon Ayres, Aberdeen University

Professor Robert Peveler, University of Southampton

Professor David Nutt, University of Bristol

Dr John Axford, St George’s University of London

Dr Russell Lane, Charing Cross Hospital, London

Dr John K Chia, UCLA Medical Centre, CA, USA

Dr Derek Enlander, NY, USA

Dr Paul Langford, Imperial College London

Professor Mike Levin, Imperial College London

FUNDING

CFS Research Foundation, Hertfordshire, UK


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