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

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 trial

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  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 phenotypecytokine 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 Enterovirus 109Chlamydia pneumoniae 18Epstein-Barr virus 6Recurrent VZV infection 6Parvovirus B19 infection 3Hepatitis C virus 3Cytomegalovirus 3Postvaccination (pn, MMR or flu) 3Toxic mould exposure 2Recurrent HHV-6 infection 1 Unknown 44 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. Hypothesis for prolonged fatigue / CFS Insults A B C D E F G H I J K Initial processes Final common pathway(s) CFS

  7. Overview of basic cell processes

  8. Microarray

  9. Microarray

  10. GENES Taqman real-time PCR Test gene Control gene

  11. 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

  12. Pilot study 16 CFS-associated Genes Immune IL-10RAIL-10 receptor alphaCD2BP2 CD2 antigen binding protein 2 Neurological PRKCL1 Protein kinase C-like 1 GABARAPL1 GABA(A) receptor associated protein like-1 KHSRP KH-type splicing regulatory proteinNTE Neuropathy target esterase GSN Gelsolin Mitochondrion MRPL23 Mitochondrial ribosomal protein L23 EIF2B4 Euk. translation initiation factor 2B, subunit 4δ, tv-1EIF4G1 Euk. Translation initiation factor 4G, subunit 1, tv-5 Apoptosis / cell cycle PDCD2 Programmed cell death 2, tv-1 ANAPC11 Anaphase promoting complex subunit 11 homolog BRMS1 Breast cancer metastasis suppressor 1 Peroxisome ABCD4 ATP-binding cassette subfamily D, member 4 PEX16 Peroxisomal biogenesis factor 16 Transcription POLR2G RNA polymerase II (DNA-directed) polypeptide G

  13. GENES

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

  15. Hypothesis A working model of CFS T lymphocyte Macrophage

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

  17. 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

  18. 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

  19. 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

  20. GENES MPSS 182 15 52 Microarray Immune ResponseNeurological genesMitochondrial genesSelective Regulation

  21. Phase-1 cont.

  22. GENES

  23. GENES

  24. GENES Human microRNAs in CFS

  25. 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)

  26. GENES Associations of CFS-associated genes with symptoms Phase 3 CFS-associatedsymptoms CFS-associatedgenes Time (12 months)

  27. GENES Virus genes in CFS 28 microbes HerpesvirusesEnterovirusesParvovirusesCoxiella burnetiiMycoplasma pneumoniae Chlamydia pneumoniaeetc.etc. MPSSStudy Known virustriggers 28 microbes

  28. TREATMENTDEVELOPMENT Clinical trials of treatment candidates Phase 4 Human Virus NFKB IL-6 Interferon-b HIF1a T cell activation Acyclovir Pleconoril Clarithromycin Interferon-b

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

  30. Biomarkers Development of a diagnostic test for CFS SELDI-PC

  31. Biomarkers SELDI-PC

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

  33. Clinical Centres

  34. 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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