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Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME): pathogenesis, diagnostic biomarkers & clinical trials Dr Jonathan R Kerr MD, PhD, FRCPath.

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Presentation on theme: "Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME): pathogenesis, diagnostic biomarkers & clinical trials Dr Jonathan R Kerr MD, PhD, FRCPath."— Presentation transcript:

1 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

2 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

3 Chronic Fatigue Syndrome (CFS) Studies of Pathogenesis Immune system -  IC’s,  IgG,  B cells,  NK Th2 phenotype cytokine dysregulation / chronic immune activation Infection - virus, bacterium Nervous system - paresis, visual loss, ataxia, confusion abnormal metabolism of 5-HIAA, A-V, 5-HT, PRL brain scan abnormalities Endocrine system -slight  HPA axis Cardiovascular system - vasodilatation Psychological function -depression & anxiety Genetic predisposition -deduced from twin studies

4 Active infections / insults in 200 CFS patients Enterovirus109 Chlamydia pneumoniae18 Epstein-Barr virus6 Recurrent VZV infection6 Parvovirus B19 infection3 Hepatitis C virus3 Cytomegalovirus3 Postvaccination (pn, MMR or flu)3 Toxic mould exposure2 Recurrent HHV-6 infection 1 Unknown44 Chia et al. Clin Infect Dis 2003;36:671-2.

5 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

6 ABCDEFGHIJKABCDEFGHIJK Hypothesis for prolonged fatigue / CFS Final common pathway(s) Insults Initial processes CFS

7 Overview of basic cell processes

8 Microarray

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10 Taqman real-time PCR GENES Test gene Control gene

11 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 Study of Gene Expression in Chronic fatigue syndrome Pilot study Pilot study

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13 16 CFS-associated Genes ImmuneIL-10RA IL-10 receptor alpha CD2BP2 CD2 antigen binding protein 2 NeurologicalPRKCL1 Protein kinase C-like 1 GABARAPL1 GABA(A) receptor associated protein like-1 KHSRP KH-type splicing regulatory protein NTE Neuropathy target esterase GSN Gelsolin MitochondrionMRPL23 Mitochondrial ribosomal protein L23 EIF2B4 Euk. translation initiation factor 2B, subunit 4δ, tv-1 EIF4G1Euk. Translation initiation factor 4G, subunit 1, tv-5 Apoptosis / cell cyclePDCD2 Programmed cell death 2, tv-1 ANAPC11 Anaphase promoting complex subunit 11 homolog BRMS1 Breast cancer metastasis suppressor 1 PeroxisomeABCD4 ATP-binding cassette subfamily D, member 4 PEX16 Peroxisomal biogenesis factor 16 TranscriptionPOLR2G RNA polymerase II (DNA-directed) polypeptide G Pilot study

14 GENES

15 A complex pathogenesis Support for a biological process in CFS Conclusion Pilot study

16 A working model of CFS Hypothesis Macrophage T lymphocyte

17 A working model of CFS Hypothesis Macrophage T lymphocyte cytokines, etc

18 What are the human and virus gene signatures of CFS? Repeat microarray study CFS patients and normal controls Determine levels of ALL human and virus genes GENES Phase 1-continued

19 Phase-1 continued Study Phase-1 cont. 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

20 Virus & Human genes in CFS Microarray study MPSS Study GENES Microarray 47,000 human genes 27 CFS pts / 54 normals East Dorset CFS Service MPSS ALL genes sequenced 20 CFS pts / 20 normals University of Cardiff

21 Microarray MPSS GENES Immune Response Neurological genes Mitochondrial genes Selective Regulation

22 Phase-1 cont.

23 GENES

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25 Human microRNAs in CFS GENES

26 Confirmation of specificity of CFS gene signature GENES 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) Phase 2

27 Associations of CFS-associated genes with symptoms Phase 3 Time (12 months) CFS-associated genes CFS-associated symptoms GENES

28 Virus genes in CFS MPSS Study GENES Known virus triggers 28 microbes Herpesviruses Enteroviruses Parvoviruses Coxiella burnetii Mycoplasma pneumoniae Chlamydia pneumoniae etc. etc.

29 Clinical trials of treatment candidates Phase 4 TREATMENT DEVELOPMENT Human Virus NFKB IL-6 Interferon-b HIF1a T cell activation Acyclovir Pleconoril Clarithromycin Interferon-b

30 Clinical trials of treatment candidates Phase 4 TREATMENT DEVELOPMENT HumanVirus Interferon-b NFKB IL-6 HIF1a T cell activation Acyclovir Pleconoril Clarithromycin

31 SELDI-PC Development of a diagnostic test for CFS Biomarkers

32 SELDI-PC Biomarkers

33 Diagnostic test for CFS Biomarkers **Collaboration with Dept of Paediatrics, Imperial College London

34 Clinical Centres

35 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 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

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