Rapidly evolving multiple sclerosis: opening the window of therapeutic opportunity

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

Multiple Sclerosis (MS) is a demyelinating disease of the nervous system that represents the most common cause of disability in young adults. It is a long-term disease with a significant medical, economic and social impact, largely due to the accumulation of disability. Results of studies and clinical practice show that patients affected by rapidly evolving form of MS may not benefit from the available immunomodulatory drugs and are at high risk to become disabled. We want to establish a group (?cohort?) of patients with very active forms of MS that has not been controlled by the standard treatments. With ethical approval and the consent of each patient who wishes to enter this cohor, we plan to study in great detail the characteristics of disease in each subject by clinical tests, brain scans, blood and spinal fluid tests for indices of inflammation and by mapping some variations of genes that are associated with MS. With this information we will be able to identify within the group the most suitable patients who could benefit from new therapies being studied. The patients participating in the cohort will have the option to participate in the clinical trial most suitable to them. By accelerating the access of candidate patients, the clinical trials will be run more efficiently, speeding up the development of effective cures for MS.

Technical Summary

Multiple sclerosis (MS) is a heterogeneous inflammatory and degenerative disease of the central nervous system that presents with a variable clinical course and a broad spectrum of severity. This heterogeneity is likely to reflect at least in part the involvement of different components to the pathogenesis of the disease, as suggested by studies of MS lesion pathology. Clinical and pathological heterogeneity in patient populations represents a difficulty in the evaluation of responses to MS therapies. However, progress in the characterisation of the components of MS pathogenesis and the increasing availability of biological agents targeting specific cell populations or functions now offer great opportunity to develop more individualised and effective therapies.

By establishing a research cohort of patients with rapidly evolving MS in a relatively early stage of disease we intend to maximise the opportunity to develop effective therapies. Our group has expertise in state-of-the-art methodologies for clinical, immunological, genetic and genome-wide transcriptional characterisation of MS phenotypes. Systematic collection of phenotypic data within the research cohort will allow delineating homogenous subgroups of patients who are appropriate candidates to clinical trials of new therapeutics. By developing search algorithms for existing or newly designed academic- or industry-driven clinical trials we will be able to rapidly and objectively identify patient subgroups with specific disease characteristics.

The products that our research cohort programme can deliver are (i) providing to patients with rapidly evolving MS the option to participate in trials of novel therapeutics exploiting the appropriate window of therapeutic opportunity, and (ii) to drive development of novel pharmacological or cell therapies through an innovative model to efficiently recruit specific patient populations.

Publications

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Atkins HL (2012) Autologous hematopoietic stem cell transplantation for autoimmune disease--is it now ready for prime time? in Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation

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Colasanti A (2014) In Vivo Assessment of Brain White Matter Inflammation in Multiple Sclerosis with (18)F-PBR111 PET. in Journal of nuclear medicine : official publication, Society of Nuclear Medicine

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Lema A (2017) A Comparison of Magnetization Transfer Methods to Assess Brain and Cervical Cord Microstructure in Multiple Sclerosis. in Journal of neuroimaging : official journal of the American Society of Neuroimaging

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Muraro PA (2010) Resetting autoimmunity in the nervous system: The role of hematopoietic stem cell transplantation. in Current opinion in investigational drugs (London, England : 2000)

 
Description AISM Research Grant
Amount £53,333 (GBP)
Organisation Italian Multiple Sclerosis Society (AISM) 
Sector Charity/Non Profit
Country Italy
Start 11/2009 
End 11/2011
 
Description Collaborative Project Grant
Amount £650,000 (GBP)
Funding ID 944/10 
Organisation Multiple Sclerosis Society 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2012 
End 04/2015
 
Description Equipment grant
Amount £239,831 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2010 
 
Description Junior Fellowship
Amount £112,768 (GBP)
Funding ID 975/12 
Organisation Multiple Sclerosis Society 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2013 
End 06/2015
 
Description Pathfinder
Amount £1,000,000 (GBP)
Funding ID MR/N026934/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 06/2016 
End 05/2019
 
Description PhD Studentship
Amount £38,732 (GBP)
Organisation Italian Multiple Sclerosis Society (AISM) 
Sector Charity/Non Profit
Country Italy
Start 04/2011 
End 04/2014
 
Description Project Grant
Amount £235,464 (GBP)
Funding ID 938/10 
Organisation Multiple Sclerosis Society 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2011 
End 05/2015
 
Description Project Grant
Amount £60,298 (GBP)
Funding ID 2010/R/24 
Organisation Italian Multiple Sclerosis Society (AISM) 
Sector Charity/Non Profit
Country Italy
Start 10/2010 
End 04/2015
 
Description Research Fellowship
Amount £63,575 (GBP)
Funding ID Prot. N. 23/13/F1 
Organisation Italian Multiple Sclerosis Society (AISM) 
Sector Charity/Non Profit
Country Italy
Start 05/2013 
End 04/2015
 
Description Research Grant
Amount £2,055,691 (GBP)
Organisation Multiple Sclerosis Society 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2009 
End 06/2014
 
Description Research Grant
Amount € 210,000 (EUR)
Funding ID 2015/R/16 
Organisation Italian Multiple Sclerosis Society (AISM) 
Sector Charity/Non Profit
Country Italy
Start 03/2016 
End 03/2018
 
Description Research Grant from Multiple Sclerosis Trial Collaboration (recognized charity)
Amount £10,000 (GBP)
Organisation Multiple Sclerosis Trials Collaboration 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2009 
End 12/2010
 
Description Research grant
Amount £40,419 (GBP)
Funding ID WMCN P36769 
Organisation Imperial College London 
Sector Academic/University
Country United Kingdom
Start 12/2011 
End 12/2012
 
Title Clinical trials database 
Description We have indexed and analysed all clinical trials in the UK for which public information exists and that would be in principle applicable to the PRCI population. A database has been created, is being periodically updated and it utilised to match PRCI subjects to clinical trials. 
Type Of Material Biological samples 
Year Produced 2010 
Provided To Others? Yes  
Impact Essential to run the PRCI cohort, this database might benefit additional users. 
 
Title Patient research cohort and biosample database. 
Description A database to enter multiple sclerosis patients data and to organize the research cohort biosample inventory were developed. 
Type Of Material Biological samples 
Year Produced 2013 
Provided To Others? Yes  
Impact The database and biosample software will support additional studies within the group and outside collaborations. 
 
Description Cambridge 
Organisation University of Cambridge
Department School of Clinical Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided biosamples from consented patients with active multiple sclerosis wishing to participate in genetics studies of the International MS Genetics Consortium.
Collaborator Contribution Provide HLA typing for immunogenetics studies and genotype/phenotype association studies.
Impact Work in progress.
Start Year 2009
 
Description Collaboration with GSK and Imanova 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution Providing anonymised, aggregate data access to a well-defined patient cohort with advanced imaging analysis and identify unmet healthcare needs.
Collaborator Contribution Developing methods and tools for stratified medicine, novel imaging methods.
Impact Workshop on stratified medicine held 5 October 2012.
Start Year 2009
 
Description Collaboration with GSK and Imanova 
Organisation Imanova
Country United Kingdom 
Sector Private 
PI Contribution Providing anonymised, aggregate data access to a well-defined patient cohort with advanced imaging analysis and identify unmet healthcare needs.
Collaborator Contribution Developing methods and tools for stratified medicine, novel imaging methods.
Impact Workshop on stratified medicine held 5 October 2012.
Start Year 2009
 
Description Natural history of MS 
Organisation University of Oxford
Department Nuffield Department of Clinical Neurosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution To provide access, analytical tools and expertise to analysis of clinical databases of MS.
Collaborator Contribution Study of natural history of MS
Impact Two publications and a funded project grant.
Start Year 2009
 
Description Participation in London Biotechnology Network 
Organisation London Biotechnology Network
Country United Kingdom 
Sector Academic/University 
PI Contribution We have participated and given a presentation in the annual event at the BioGuide London Symposium "Ageing & CNS/Neurodegenerative Disorders" , a business network of over 800 organisations/2000 members from the biopharmaceutical sector, academia and other partners. The event was held at the UCL Institute of Neurology.
Collaborator Contribution The partnership has allowed us to share information about the project with the Network, which has been followed by increased contacts with industry and academic colleagues that have the potential to evolve into collaboration and partnership.
Impact Publication of the Bioguide London (Ageing and CNS/Neurodegenerative Disorders) directory published by the LBN and available online at www.londonbiotechnology.co.uk.
Start Year 2009
 
Title Clinical Trial of MSC in MS 
Description Running the first randomised controlled trial of mesenchymal stem cell therapy in active multiple sclerosis that received MHRA clinical trial authorisation (CTA) as advanced therapy medicinal product (ATMP). 
Type Therapeutic Intervention - Cellular and gene therapies
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2012
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Established a regulatory approval precedent and feasibility of the intervention. 
URL http://clinicaltrials.gov/show/NCT01606215
 
Description Barts and the London NHS Trust multiple sclerosis study day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact Over 200 patients and their families together with health professional attended the meeting. We had both a talk given by the PI introducing the patient research cohort initiative and a poster presented by the Research Nurse and the PI that was well attended. We also distributed printed referral information.

Disseminating the PRCI resulted in some patient self-referrals to the Cohort as well as increased awareness by clinicians at Barts and the London NHS Trust about our initiative.
Year(s) Of Engagement Activity 2010
 
Description MS Study day 2012 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact Describe current clinical trials and research

Patient enquiries about trials
Year(s) Of Engagement Activity 2012
 
Description MS study day 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact >200 patients with MS and their families attended a presentation at this MS study day. Excellent feedback was returned.

Increased recruitment in the research cohort
Year(s) Of Engagement Activity 2011,2012,2013
 
Description Meet the scientist annual day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact The event consisted of an open day in our labs at the Burlington Danes Building, Hammersmith Campus, Imperial College for people with Parkinson's, Alzheimer's and MS and the aims are both to help them learn about research on the disorder that affects them and to provide an opportunity for basic (non-clinical) researchers to connect with and be inspired in their research by real people with the disease they are studying.

Questionnaire results revealed that the majority found day enjoyable, informative and accessible to participants.
Year(s) Of Engagement Activity 2012,2013,2014
 
Description Research Matters magazine 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact Article about the MRC funded project was published in the MS matters magazine, a quarterly magazine printed and distributed nationally and also available online for people with MS and healthcare professionals.

Increased number of self-referrals.
Year(s) Of Engagement Activity 2011
 
Description Study day on MS Treatments: the next steps 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact An information up-date study day for people with MS, their relatives, and clinicians was held at Ealing Town Hall on March 24th 2010. The meeting was attended by >100 patients and by representatives of the MS Society and the MS Trust. Updates on treatments and clinical trials including the PRCI Rapidly evolving MS were presented and discussed with the patients.


Majority of Participants' evaluation form return rated very high or high the quality of information presented in the MS study day. An increased interest in participating in clinical trials was noted in patients attending the MS service at Charing Cross Hospital.
Year(s) Of Engagement Activity 2010,2013,2014