Sampling and biomarker OPtimisation and Harmonisation In ALS and other motor neuron diseases (SOPHIA)

Lead Research Organisation: University of Sheffield
Department Name: Neurosciences

Abstract

Amyotrophic Lateral Sclerosis (ALS) is one of the most devastating diseases in neurology affecting some 50,000 individuals at any time in Europe, and causing around 10,000 deaths each year. The main clinical features are weakness and wasting of muscles, but dementia may also occur. ALS represents a good model for study of all neurodegenerative conditions, as it has a characteristic phenotype, rapid progression and the correlation between diagnosis during life and autopsy diagnosis is close to 100%. However, validated neurochemical biomarkers for monitoring disease activity, for generating earlier diagnoses and for defining prognosis are lacking. Active European collaborations are in place for harmonizing clinical datasets, neuroimaging and neuropathology protocols. A preliminary strategy for harmonization of biological and tissue samples has been established. Standardized protocols for clinical data and sample collection are now urgently required for optimization and harmonization of biomarker development.
The overall aim of this proposal is to provide a common European strategy for the prioritization and selection of candidate biomarker domains for optimization and harmonization. This will in turn provide a long-term platform by which existing collaborative structures that are relevant to neurodegenerative disease biomarkers (including academic initiatives, co-funding strategies, biobanks, industrial efforts, private-public alliances) are integrated within an inclusive web-based virtual biobank. Samples and clinical/imaging/neurophysiologic and neuropathological datasets provided by participating members can then be optimally utilized to enable state of the art collaborative analyses.
The established platform will also act as an important communication channel between this consortium and the rest of the ALS/Neurodegeneration field to ensure that the optimization efforts are in line with the whole ALS/ND field, to avoid duplication of work, and to ensure better acceptance and utilization of the project results by all stakeholders. Ultimately, the platform will be used to disseminate the results to the whole ALS/Neurodegeneration field, and will act as a permanent Interactive European ALS biomarker platform for researchers to optimize/harmonize novel biomarkers using an established pan-European ALS methodology. The platform will also allow interaction with those of other cognate groups (e.g the NEALS group within the US) and with patient groups and other relevant stakeholders.

Technical Summary

Amyotrophic Lateral Sclerosis (ALS) is one of the most devastating diseases in neurology affecting some 50,000 individuals at any time in Europe, and causing around 10.000 deaths each year. The motor system (upper motor neurons in the motor cortex and lower motor neurons in the spinal cord) is preferentially affected. Whilst correlation between clinical and autopsy diagnosis is close to 100%, validated neurochemical biomarkers for monitoring disease activity, earlier diagnosis and defining prognosis are lacking. Thus, standardized protocols for clinical data and sample collection are now urgently required for optimization and harmonization of biomarker development.
The overall aim of this proposal is to provide a common European strategy for the prioritization and selection of candidate biomarker domains for optimization and harmonization. This will in turn provide a long term platform by which existing collaborative structures that are relevant to neurodegenerative disease biomarkers (including academic initiatives, co-funding strategies, biobanks, industrial efforts, private-public alliances) are integrated within an inclusive web-based virtual biobank. Samples and clinical, imaging, neurophysiologic and neuropathological datasets provided by participating members can then be optimally utilized to enable state of the art collaborative analyses. The established platform will act as an important communication channel between this consortium and the broader international ALS/Neurodegeneration field, to ensure that the optimization efforts are consistently applied. Ultimately, the platform will establish a permanent Interactive European ALS biomarker tool for all researchers, and will enable ongoing optimization/harmonization of novel biomarkers using an integrated and robust pan-European ALS methodology. The platform will allow interaction with those of other cognate groups (e.g the NEALS group within the US), with patient groups and other relevant stakeholders.

Planned Impact

ALS is one of the most devastating neurodegenerative diseases for which no therapy exist. As such, the existence of a set of optimized and standardized methods for collection, preservation and analysis of different biomarkers necessary to evaluate diagnosis and disease progression of ALS and other motor neuron diseases will be an enormous advance in the investigation of this condition at several levels, possibly transferable to other forms of neurodegeneration.

The impact would involve many different areas:

1- Systematic multicentre investigation to permit an earlier and more reliable diagnosis has two major implications:
a. Less time consuming expensive investigations before reaching the final diagnosis of ALS, avoiding unnecessary interventions such as surgical procedures
b. Earlier clinical trial entry with high chances of defining an effective drug
2- All methods, database, biomarker essays, and biomarker in SOPHIA will be shared with other members of the scientific community devoted to ALS and to other ND.
3- The concept of this project (pan-European SOPs) can be expanded to other ND resulting in a driving force for shared biomarker research.
4- Better understanding of ALS etiopathogenesis and natural history.
5- The project will increase the interest of the international scientific community in relation to ALS.
6- Identification of consistent biomarker in ALS will permit less expensive, smaller, and shorter trials with better stratified early ALS patients, with increased probability to find an effective drug.
7- Availability of more precise measures of disease activity and disease progression will improve trial design and thereby attract pharmaceutical industry to investigate new compounds in ALS.
8- Improved patient care as a systematic questionnaire is applied to permit a proper evaluation. A potential biomarker will allow a more scientific evaluation of all interventions.
9- Patients association satisfied with higher care quality: all interventions will be more appropriately measured due to this project.
10- The finding of potential biomarker(s) will allow the development of new European commercial opportunities to develop biomarker detection kits for use in neurodegeneration clinical practice.
11- The project will demonstrate the impact of a large European multicentric project in relation to a relatively rare disorder acting as a template for other conditions in the future.
12- SOPHIA will for the first time establish an Interactive European ALS biomarker website, that serves as a vehicle to support implementation of the pan-European methodology on ALS biomarker optimization and harmonization. This platform engages with end-users in an early stage, thereby improving acceptation and implementation of project results by these stakeholders. Possibilities for co-funding and member fees will be examined to ensure that this platform will be sustainable. When successful, this platform can be extended to / implemented in other ND areas.

Publications

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Verber NS (2019) Biomarkers in Motor Neuron Disease: A State of the Art Review. in Frontiers in neurology

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Beer AM (2016) Case report of concurrent Fabry disease and amyotrophic lateral sclerosis supports a common pathway of pathogenesis. in Amyotrophic lateral sclerosis & frontotemporal degeneration

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Fang T (2017) Comparison of the King's and MiToS staging systems for ALS. in Amyotrophic lateral sclerosis & frontotemporal degeneration

 
Description 2015-2018 £247,954. Bioenergetic profiling of cellular ALS models (MNDA Senior Non-Clinical Fellowship - Scott Allen, Allen/Oct15/956-799).
Amount £247,954 (GBP)
Funding ID Allen/Oct15/956-799 
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2015 
End 09/2018
 
Description A multicentre biomarker resource strategy in ALS: AMBRoSIA.
Amount £2,576,509 (GBP)
Funding ID Turner/Oct15/972-797 
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2016 
End 07/2020
 
Description CoEN PATHFINDER III
Amount £554,199 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2018 
End 04/2020
 
Description MIROCALS (modifying immune response and outcomes in ALS). Efficacy and safety of low-dose IL-2 (Id-IL-2) as a Treg enhancer for anti-inflammatory therapy in newly diagnosed amyotrophic lateral sclerosis (ALS) patients.
Amount £5,980,436 (GBP)
Funding ID 633413 
Organisation European Economic Community 
Sector Public
Country European Union (EU)
Start 05/2015 
End 05/2018
 
Description NIHR Biomedical Research Centre: Translational Neuroscience for Chronic Neurological Disorders
Amount £4,049,681 (GBP)
Organisation National Institute for Health Research 
Department NIHR Biomedical Research Centre
Sector Public
Country United Kingdom
Start 03/2017 
End 03/2022
 
Description The generation and characterisation of stem-cell derived astrocytes, from skin biopsies of genetic subgroups of motor neuron disease.
Amount £105,185 (GBP)
Organisation Government of Saudi Arabia 
Sector Public
Country Saudi Arabia
Start 01/2015 
End 07/2016
 
Title Cerebrospinal fluid biosamples to Dr Markus Otto in Ulm 
Description Cerebrospinal fluid from ALS cases and controls was sent to Markus Otto at Ulm University, Germany to perform measurement of specific biomarkers associated with ALS. This work demonstrated the variability in samples between European centres, due to sample collection, handling and storage. 
Type Of Material Biological samples 
Year Produced 2015 
Provided To Others? No  
Impact Publication submitted to "Amyotrophic lateral sclerosis and frontotemporal degeneration" 
 
Title Contributed to multi-centre assessment of imaging biomarkers of disease progression in ALS/MND. 
Description Standardised method for collecting data from patient MRI scans applicable to multi-centre studies. 
Type Of Material Physiological assessment or outcome measure 
Provided To Others? No  
Impact Will facilitate multicentre biomarker analysis of imaging parameters. 
 
Title Development of MUNIX for neurophysiological assessment of MND patients. 
Description A method for quantifying motor neuron numbers over the disease course. 
Type Of Material Physiological assessment or outcome measure 
Provided To Others? No  
Impact A quantitative tool for assessment of motor neuron numbers which can be used in multi centre studies over the disease course. 
 
Description 29th ALS/MND International Symposium Glasgow, December 2018. Closing Plenary lecture. Physical activity as a risk factor for ALS/MND. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Over 1,200 delegates attended the closing plenary lecture. The International Symposium on ALS/MND has a deserved reputation for bridging the gulf between science and clinical
practice and I have subsequently embarked on a multidisciplinary collaboration with Sheffield colleagues to investigate the role of physical activity as a risk factor in ALS further.
Year(s) Of Engagement Activity 2018
URL https://www.mndassociation.org/symposium/wp-content/uploads/2018/11/PROGRAMME-FINAL-WEB-VERSION-1.pd...
 
Description ENCALS Meeting May 2015 Dublin C9ORF72 repeat expansions produce distinctive metabolic profiles in human CNS tissue. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Scientific presentation of original research at the European Network for the Cure of ALS (ENCALS). The ENCALS meeting is an important forum for the European MND community. The aim of the meeting is to encourage younger researchers to present their data, and to meet and interact with more established members of the community.
Year(s) Of Engagement Activity 2015
URL https://www.encals.eu/wp-content/uploads/2016/12/Programme_ENCALS_meeting2015.pdf
 
Description Target validation in ALS/MND meeting, London April 2018. The Nrf2-ARE pathway as a therapeutic target in ALS/MND 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact .
Year(s) Of Engagement Activity 2018