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

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 Georges University of London

2
Chronic Fatigue Syndrome (CFS)
Epidemiology Prevalence of 0.5 More common in
females (61) 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 - ?ICs,
?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
Enterovirus 109Chlamydia pneumoniae 18Epste
in-Barr virus 6Recurrent VZV
infection 6Parvovirus B19 infection 3Hepatit
is C virus 3Cytomegalovirus 3Postvaccinati
on (pn, MMR or flu) 3Toxic mould
exposure 2Recurrent HHV-6 infection
1 Unknown 44
Chia et al. Clin Infect Dis 200336671-2.
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
Taqman real-time PCR
GENES
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
(No Transcript)
13
16 CFS-associated Genes
Pilot study
Immune IL-10RA IL-10 receptor alpha CD2BP2
CD2 antigen binding protein 2 Neurological PRKCL
1 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 Mitochondrion MRPL23 Mitochondrial
ribosomal protein L23 EIF2B4 Euk.
translation initiation factor 2B, subunit 4d,
tv-1 EIF4G1 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
14
GENES
15
Pilot study
Conclusion

• A complex pathogenesis
• Support for a biological process in CFS

16
Hypothesis
A working model of CFS
T lymphocyte
Macrophage
17
Hypothesis
A working model of CFS
T lymphocyte
Macrophage
cytokines, etc
18
What are the human and virus gene signatures of
CFS?
GENES
Phase 1-continued
Repeat microarray study CFS patients and normal
controls Determine levels of ALL human and virus
genes
19

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
20
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
21
GENES
MPSS

• Microarray

15
52
182
Immune ResponseNeurological genesMitochondrial
genesSelective Regulation
22

Phase-1 cont.
23
GENES
24
GENES
25
GENES
Human microRNAs in CFS
26
GENES
Confirmation of specificity of CFS gene signature
Phase 2
Idiopathic CFS (n500) Infection-associated CFS
(n50) Prolonged fatigue (n50) Normal fatigue
(n25) Normals (n100) Rheumatoid arthritis
(n50) Osteoarthritis (n50) Endogenous
depression (n50)
27
GENES
Associations of CFS-associated genes with symptoms
Phase 3
CFS-associatedsymptoms
CFS-associatedgenes
Time (12 months)
28
GENES
Virus genes in CFS
28 microbes HerpesvirusesEnterovirusesParvoviru
sesCoxiella burnetiiMycoplasma pneumoniae
Chlamydia pneumoniaeetc.etc.
MPSSStudy
Known virustriggers
28 microbes
29
TREATMENTDEVELOPMENT
Clinical trials of treatment candidates
Phase 4
Human
Virus
NFKB IL-6 Interferon-b HIF1a T cell activation
Acyclovir Pleconoril Clarithromycin Interferon-b
30
TREATMENTDEVELOPMENT
Clinical trials of treatment candidates
Phase 4
Human
Virus
NFKB IL-6 HIF1a T cell activation
Acyclovir Pleconoril Clarithromycin
Interferon-b
31
Biomarkers
Development of a diagnostic test for CFS

• SELDI-PC

32
Biomarkers
SELDI-PC
33
Biomarkers
Diagnostic test for CFS
Collaboration with Dept of Paediatrics,
Imperial College London
34
Clinical Centres
35
Acknowledgements
STUDY DESIGN LABORATORY WORK Deepika Devanur,
St Georges University of London Robert Petty, St
Georges University of London Beverley Burke, St
Georges 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 Georges 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

36
(No Transcript)