Presentation on theme: "Research: State of the Art Professor Derek Pheby."— Presentation transcript:
Research: State of the Art Professor Derek Pheby
Where are we starting from? (1) What we know: ME is a syndrome (defined by its symptoms, not underlying pathology) Characterised by multi-system dysfunction Varies in severity and duration Acute or insidious onset Range of trigger factors, frequently viral Most common in women, particularly young adults (though occurs at all ages)
Where are we starting from? (2) What we don’t know Underlying pathology – one disease or several? How to treat it
Where are we starting from? (3) Common myths: It doesn’t exist! If it does exist, it’s a psychological condition NICE has had the last word on the subject Graded exercise and cognitive behaviour therapy are effective treatments
The Pathophysiology of ME –Cause or Effect? Hypothalamic-pituitary dysfunction Neuromuscular abnormalities Abnormal serum cortisol Abnormal patterns of cytokine expression Abnormal patterns of gene expression Mitochondrial dysfunction Oxidative stress
Research Activity (1) Published scientific papers: US 50% UK 30% Rest of world 20% - but it doesn’t really amount to a coherent corpus of scientific knowledge
Research Activity (2) Why has all this work not advanced knowledge further? Vicissitudes of funding No coherent strategy No supportive infrastructure
The Observatory project (1) Funded for three years by the Big Lottery Fund Sponsored by Action for ME Academic collaboration of three universities: London School of Hygiene and Tropical Medicine University of Hull University of East Anglia
The Observatory project (2) Purpose: Fill gaps in knowledge Epidemiology Qualitative social research Create range of infrastructure facilities to support research
The Observatory project (3) Output to date: Six scientific papers published Disease Register Services Directory
The Observatory project (4) New projects: Biobank Post Mortem tissue archive
The Biobank Aims : To develop a key resource for biomedical research, especially the investigation of biomarkers for diagnosis and prognosis.
The Biobank (2) Specific main objectives: to establish a biobank for the study of ME/CFS, as a resource for high quality and ethically approved biomedical research studies benefiting from well catalogued blood samples, which are linkable to clinical and risk factors data; to investigate risk factors for severity; to correlate clinical phenotype with disease severity.
The Biobank (3) Subsequently: to disseminate the resource to the research community to plan high throughput studies, benefiting from sample collections and rapid advancing sequencing (e.g. whole genome sequencing,) and other molecular techniques, such as those investigating immune and genetic biomarkers to link the Biobank to the planned ‘post- mortem’ tissue bank for the study of ME/CFS.
The Biobank (4) Outcomes full implementation of the ME/CFS Biobank, including: recruitment of well characterised cases with ME/CFS and controls, blood sample collections and storage.
The Biobank (5) Other Research Possibilities Linkage of data from stored biological samples with longitudinal clinical data from the Disease Register will enable identification of clinical and pathological factors associated with particular adverse outcomes of interest. e.g. what clinical and pathological factors may be associated with disease severity? This will contribute to the development of prevention strategies
The Biobank (6) $1.5 million awarded by National Institutes of Health, Washington DC Making possible a very large increase in the scale of the project
The Biobank (7): The NIH Project Aims (i) i)to investigate risk factors for disease severity; ii)to correlate clinical phenotype with disease severity; iii)to disseminate the resource to researchers and others iv)to plan high throughput studies.
The Biobank (8): The NIH Project Aims (ii) High throughput studies will benefit from:- sample collections; rapidly advancing molecular techniques, e.g. investigating immune and genetic biomarkers; expansion of the Disease Register; link to post-mortem tissue bank for the study of ME/CFS.
More Information http://www.lshtm.ac.uk/itd/crd/ research/cure-me/index.html
Post Mortem Tissue Archive – Pros & Cons Rationale To create an opportunity to study neurological and other tissues from people with ME, in order to investigate underlying disease processes. Post mortem tissue archives have been established and function effectively in other neurodegenerative diseases, and one for ME exists in the US
Post Mortem Tissue Archive – Pros & Cons Problems Logistics of specimen handling Cost Time
Post Mortem Tissue Archive – Feasibility Study ME has rarely been studied in post-mortem examinations, despite evidence of abnormalities from neuroimaging. Aim: To ascertain the feasibility of developing a national post-mortem ME/CFS tissue bank in the UK. Method: Case study, involving key informant interviews, focus group of PWME, workshop with experts Results suggested that post-mortem tissue bank was desirable, feasible, and acceptable to possible donors. Lacerda EM, Nacul L, Pheby D, Shepherd C, Spencer P. Exploring the feasibility of establishing a disease-specific post-mortem tissue bank in the UK: a case study in ME/CFS. J Clin Pathol (2010); 63: 1032-1034.
Other Initiatives: MRC Euromene US Department of Defense
The MRC Initiative £1.6 million allocated, following work of Expert Group, for call entitled: “Understanding the Mechanisms of CFS/ME” Closing date 7 June 2011.
MRC (2) - Aims Support high-quality, innovative research that increases the CFS/ME knowledge base; Address the mechanisms underlying chronic changes in CFS/ME, particularly: Autonomic dysfunction Cognitive symptoms Fatigue Immune dysregulation Pain Sleep disorders
MRC (3) – Aims (continued) Enhance understanding through study of cross-disease symptomology Address lack of capacity in CFS/ME research, and need for multidisciplinary teams Involve partnerships between CFS/ME researchers and leading investigators in other fields.
MRC (4) - The Five Funded Projects Identifying the biological fingerprints of fatigue Dr Wan Ng, Newcastle University Understanding the pathogenesis of autonomic dysfunction in chronic fatigue syndrome and its relationship with cognitive impairment Professor Julia Newton, Newcastle University Modulation of aberrant mitochondrial function and cytokine production in skeletal muscle of patients with CFS by supplementary polyphenols Professor Anne McArdle, Universities of Liverpool & Leeds Can enhancing slow wave sleep SWS improve daytime function in patients with CFS? Professor David Nutt, Imperial College London Persistent fatigue induced by interferon-alpha: a new immunological model for chronic fatigue syndrome Dr Carmine Pariante, King’s College London
MRC (5) - Identifying the biological fingerprints of fatigue Aims: To improve understanding of the mechanisms of fatigue by: analysing the immune systems of > 500 patients with primary Sjögren syndrome identifying immune system abnormalities in these patients in order to help identify the “biological fingerprints” of fatigue, hopefully leading to: new treatments. a clinical diagnostic test for CFS/ME.
MRC (6) - Understanding the pathogenesis of autonomic dysfunction in CFS and its relationship with cognitive impairment Aims: To explore the causes of autonomic nervous system dysfunction (→ dizziness and light- headedness in 90% of PWME), using fMRI to measure changes in brain blood flow to the brain relating this to cognition and nervous system dysfunction, in order to lay the foundations for: new diagnostic tools better understanding of nervous system abnormalities development of targeted treatments
MRC (7) Modulation of aberrant mitochondrial function and cytokine production in skeletal muscle of patients with CFS by supplementary polyphenols Aim: To use a newly-developed technique to study muscle mitochondria, in order to: learn more about how CFS/ME develops and becomes chronic
MRC (8) - Can enhancing slow wave sleep improve daytime function in patients with CFS? Aims: To study sleep disturbance in CFS/ME. To measure the effect of drug-induced deep restorative sleep in CFS/ME patients on brain function while awake. To increase understanding of the impact of sleep disturbance CFS/ME sufferers, in order to develop new treatments.
MRC (9) - Persistent fatigue induced by interferon-alpha: a new immunological model for CFS Aims: To study patients undergoing IFN-alpha treatment for Hepatitis C [NB IFN-alpha induces fatigue] To identify resultant biological changes, hopefully leading to: a check-list of blood measures to predict who will develop CFS/ME identification of new targets for therapy.
MRC (10) - Conclusions Common Themes: Analogies with other illnesses Start with symptoms Explore underlying disease mechanisms Based on improved understanding of pathology, develop new diagnostic tests &/or treatments
EUROMENE 30+ participating centres in 15 countries; Just submitted proposal to EU for €6 million to support collaborative research as part of the Horizon 2020 programme; Title: “Understanding ME/CFS: elucidating determinants, risk factors and pathways, in order to develop personalised preventive, diagnostic and therapeutic strategies”
EUROMENE (2): Aims of the proposed project Increasing understanding of ME/CFS by:- mapping knowledge in a systems medicine model, enriched with novel nanoanalytical, new generation sequencing, proteome analysis data, and PET studies; developing an integrated translational platform incorporating new and existing knowledge, and well characterised patient cohorts in seven EU countries; leading to new diagnostic and therapeutic products, and optimal prevention and treatment strategies.
Rituximab (1) A monoclonal antibody against the protein CD20, found on the surface of B lymphocytes. Function Rituximab destroys normal and malignant B cells that have CD20 on their surfaces.
Rituximab (2) Uses To treat diseases with excessive numbers, overactive or dysfunctional B cells, e.g. leukaemias, lymphomas, including Hodgkin's disease, also autoimmune diseases, e.g. rheumatoid arthritis, lupus, autoimmune haemolytic anaemia, in patients not responding to anti-TNF-alpha therapy.
Rituximab (3) – Pilot Study A CFS patient undergoing chemotherapy for Hodgkin's disease experienced transient CFS recovery, thought to be related to methotrexate, which induces immunomodulation partly through B-cell depletion. Subsequently, this patient and two others were B-cell depleted by rituximab infusion All three showed improvement of all CFS symptoms. Fluge O., Mella O. Clinical impact of B-cell depletion with the anti-CD20 antibody rituximab in chronic fatigue syndrome: A preliminary case series. 2009 BMC Neurology 9
PACE: Definitely not the last word (1) Significant weaknesses admitted: Only studied people with mild and moderate illness: Oxford case definition Extended criteria to improve recruitment “Standard medical care” inadequate. No objective or consistent outcome assessment
PACE: Definitely not the last word (2) Other weaknesses: Intention to treat analysis poorly applied Exaggerated claims regarding outcomes Improvements marginal for all therapies Many showed no improvement However, adverse consequences were rare.
Xenotropic Murine Leukemia Virus–Related Virus (XMRV) 2009: Lombardi et al (Whittemore-Peterson Institute University of Nevada, Reno, NV) report XMRV, a gammaretrovirus in 67% of patients (67%) compared to 3.7% of healthy controls. Numerous subsequent studies fail to replicate this finding Meanwhile, Mikovits et al (Whittemore-Peterson Institute) cast doubt on their own analyses. Consensus emerges that DNA or RNA contamination of test kits is very likely.
Action for ME Pilot Studies (May 2012) Dr Phil Manning and Prof Julia Newton, Newcastle University. Understanding muscle dysfunction in M.E./CFS: developing a drug pre-testing system Understanding muscle dysfunction in M.E./CFS: developing a drug pre-testing system Dr Jason Ellis, Northumbria University: A case controlled study exploring the qualitative experience of sleep, the roles of sleep architecture and diurnal patterns of salivary cortisol in M.E./CFS A case controlled study exploring the qualitative experience of sleep, the roles of sleep architecture and diurnal patterns of salivary cortisol in M.E./CFS Prof Annalena Venneri, University of Sheffield: Uncovering the biological correlates of cognitive impairment associated with fatigue in M.E./ CFS: a pilot study of cognition and functional connectivity pre and post-exertional malaise. Uncovering the biological correlates of cognitive impairment associated with fatigue in M.E./ CFS: a pilot study of cognition and functional connectivity pre and post-exertional malaise