JPND Biological Resource Analysis to Identify New MEchanisms and phenotypes in Neurodegenerative Diseases (BRAIN-MEND)

Lead Research Organisation: King's College London
Department Name: Clinical Neuroscience

Abstract

Neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, corticobasal degeneration, multiple system atrophy and progressive supranuclear palsy. We currently classify and treat these conditions based on symptoms and clinical findings. Although this approach seems logical it does not take into account the causes of each condition or any overlap between them, which hinders the development of new treatments. A better approach would be to reclassify the different conditions based on their causes, because this would require a deep but different understanding of each condition, and new treatments could then be directly aimed at the cause. This reclassification, new understanding, and exploration of possible treatments, is the idea behind BRAIN-MEND. We will use three innovative approaches, pioneered and developed by the BRAIN-MEND consortium. We will use the latest methods in genetics and epigenetics to identify the causes of neurodegenerative diseases, and which cell systems they affect. We will use a cutting edge technique (based on a method called network analysis) to identify new drug targets from the genetic and epigenetic results. At the same time, will use machine learning to analyse medical literature and patient records to find new or under-recognized clusters of symptoms and other clinical features which might suggest new disease groups. These three different approaches: finding causes, finding drug targets, finding new disease groups, will act to complement each other so we can be sure of any new findings. A key outcome of BRAIN-MEND will be to disentangle the different neurodegenerative diseases, so that for any patient group, we understand how different causes produce the same clinical picture, while in other cases, the same cause can produce different clinical pictures. Having this new way of thinking of neurodegenerative diseases will enhance our understanding of them and make it easier to develop new treatments. Patients and caregivers will be intimately involved throughout the project, through participation in study design, and for example, development of a patient-orientated website. BRAIN-MEND partners are highly qualified to perform the work proposed, with outstanding scientific track records, direct access to the data to be studied, and expertise in the scientific methods that will be used. All the results will be publicized through medical literature, presentation at international conferences, through a consortium blog, through social media, and through the press offices of the institutions involved.

Technical Summary

Current classification of neurodegenerative diseases (ND) is based on clinical phenotypes and does not account for underlying disease heterogeneity or overlapping disease mechanisms, hindering therapy development. Reclassification of NDs is therefore urgently needed. From a therapeutic perspective, reclassification should be based on causal and druggable factors. BRAIN-MEND will reclassify existing phenotypes using pathway and network analyses within and across complex NDs including Alzheimer Disease, Parkinson Disease, ALS, FTD, Corticobasal Degeneration, MSA, and PSP. We will use three innovative approaches, pioneered or adopted by the consortium: WP1 will apply the latest methods to identify causal genetic factors acting on molecular pathways; WP2 will apply cutting edge methods to identify epigenetic factors associated with molecular pathways of ND; and WP3 will identify drug targets from network analyses using results from WP1 and WP2 without requiring prior knowledge of mechanism. WP4 will use analysis of medical literature and patient records to identify novel or under-recognized clusters of related clinical features. These complementary approaches allow for iterative cross-validation of elucidated factors by WP1-4. BRAIN-MEND will reclassify ND phenotypes based on biologically meaningful categories corresponding to subgroups (heterogeneity) and common pathways (pleiotropy) to enhance disease understanding and facilitate drug development across the entire complex ND landscape. WP5 will manage the project and disseminate results. Patients and caregivers will be intimately involved throughout the project. Our consortium is highly qualified to perform the work proposed, as evidenced by a mean PI h-index of 61, major impact in research in neurodegeneration and neuropsychiatry, direct expertise with and access to a large and rich dataset spanning all complex NDs, track record in cross disorder analyses, and the related tools, biobanks and cell models needed.

Planned Impact

BRAIN-MEND holds the potential to directly impact the clinic, as the overall goal is to reclassify neurodegenerations in the clinically most meaningful way, namely by shared causation and treatment profile. Table 4 summarises the main exploitable results to aid the implementation of the new classification system.

Table 4. Exploitable results and their impact

1 Ranking of known drugs for each disorder (WP3) -
Potential to help prioritise drug repositioning efforts for neurodegenerative disorders.

2 Novel small molecule identification (WP3) -
Similarly, we will rank small molecules with known protein binding profiles. These will
require more careful work-up but also represent a valuable IP and general
opportunity.

3 New neurodegenerative disease loci and genes (WP1, WP2, WP3) -
New neurodegenerative disease loci will yield new neurodegenerative disease genes
through our analyses. These potentially form high priority targets for follow-up
functional work that falls beyond the scope of this grant proposal.

4 Methods and Software (WP1, WP2, WP3) -
The funding requested does not cover method development and software. However, the
data and analysis aims are likely to spin off new questions which may need to be
addressed by new methods. We have track records in method development, hence, an
indirect outcome may be new methods and software.

5 Biomarkers (WP4) -
A list of new potential biomarkers to aid neurodegenerative disease (sub) diagnosis.

6 New classification system (WP4) -
A new classification system that groups neurodegenerative diseases according to
respectively common causative pathways, treatment profile and phenotype, which
comes with guidelines for implementation, including new potential biomarkers (see
above), as well as guidelines for consistent data collection across neurodegenerative
diseases for further research to extend and fine-tune the classification system.

Neurodegenerations and neuropsychiatric diseases impact the sexes differentially both in risk and in clinical presentation. Gender differences are therefore a fundamental part of our hypotheses, aims and work plan. BRAIN-MEND will identify sex differences and the factors mediating those sex differences. For example, our analyses in WP1 and WP2 may be informed by sex-specific eQTL, mQTL and meQTL. Socio-economic factors influencing disease will be studied through analysis of geocoding and environmental questionnaire data where available. We also give a high priority to gender balance in the research team; two of the five WP leaders are women.

The BRAIN-MEND consortium acknowledges that training of young researchers and mobility within the consortium will be beneficial for maximal knowledge transfer. Therefore, consortium partners will between them exchange at least six (PhD) students or postdoctoral researchers for 2 to 4 months during the duration of this project, and provide placement on the King's College London SGDP Summer School in Bioinformatics. The aim will be to exchange knowledge of the main research techniques between consortium members. At the project start an exchange plan will be constructed. Knowledge exchange between BRAIN-MEND and other research organizations will mainly occur through interactions with relevant external transnational initiatives.

Publications

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Al Khleifat A (2019) Telomere length is greater in ALS than in controls: a whole genome sequencing study. in Amyotrophic lateral sclerosis & frontotemporal degeneration

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Al Khleifat A (2021) Intuitive Staging Correlates With King's Clinical Stage. in Amyotrophic lateral sclerosis & frontotemporal degeneration

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Al-Chalabi A (2021) Clinical staging in amyotrophic lateral sclerosis: analysis of Edaravone Study 19. in Journal of neurology, neurosurgery, and psychiatry

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Al-Chalabi A (2018) Stage of prolonged survival in ALS - Author's reply. in The Lancet. Neurology

 
Title BRAIN-MEND logo design 
Description A logo for the JPND BRAIN-MEND consortium 
Type Of Art Image 
Year Produced 2018 
Impact The consortium now has a logo 
 
Title Facebook interview about Project MinE 
Description Interview on the number of samples needed for Project MinE whole genome sequencing 
Type Of Art Film/Video/Animation 
Year Produced 2018 
Impact Many views and increased participation in Project MinE by the public 
URL https://www.facebook.com/watch/?v=1033239280173042
 
Title Livestream of talk 
Description Livestream video of a talk 
Type Of Art Film/Video/Animation 
Year Produced 2019 
Impact The video has been widely viewed and remains available for patients and the public. 
URL https://www.youtube.com/watch?v=KRb1HWv08gQ
 
Title PPI video for MND Association 
Description Video interview by MND Association for Twitter 
Type Of Art Film/Video/Animation 
Year Produced 2019 
Impact Viewed many times by symposium attendees and the public 
URL https://twitter.com/mndassoc/status/1201961917117583362
 
Title YouTube educational video on ALS 
Description Educational video on ALS research available on YouTube 
Type Of Art Film/Video/Animation 
Year Produced 2018 
Impact Patient information and understanding about ALS and research 
URL https://www.youtube.com/watch?v=7KVSbwe7bHo
 
Description Affected MND genetic testing protocols nationally
Geographic Reach National 
Policy Influence Type Contribution to new or improved professional practice
Impact Genetic testing in MND is no longer restricted to those under 40 or those with a positive family history. The evidence supporting the change was published here: https://pubmed.ncbi.nlm.nih.gov/36162820/
 
Description COVID guidance for patients
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact Worked with the Motor Neurone Disease Association to provide national advice to patients with MND during the COVID pandemic, improving quality of life and reducing risk of infectiob, hospitalization and death.
URL https://www.mndassociation.org/about-mnd/coronavirus-and-mnd/
 
Description COVID guidelines for shielding
Geographic Reach National 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
Impact Advice given to the Chief Medical Officer (via the DCMO's office) regarding shielding for people with motor neuron disease. As a result, communications were put in place through the Royal College of General Practitioners and training made available to GPs.
 
Guideline Title Guideline on clinical investigation of medicinal products for the treatment of amyotrophic lateral sclerosis (ALS)
Description Citation in European Medicines Agency (EMA) Guidelines
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact Clinical staging is being used as an endpoint for clinical trials improving understanding of the timing of treatment impact, health economics impact of treatment, and making trials more efficient.
URL https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-investigation-medicin...
 
Guideline Title Amyotrophic Lateral Sclerosis: Developing Drugs for Treatment Guidance for Industry
Description Citation of ALS clinical staging in FDA guidelines for clinical trials
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact Recommendation for commercial and academic-led trials in ALS to consider disease stage for inclusion and outcome
URL https://www.regulations.gov/document?D=FDA-2013-N-0035-0973
 
Guideline Title Clingen Gene Curation Expert Panel for ALS
Description Expert member of Clingen Gene Curation Expert Panel for ALS
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact A curated list of each gene reported as implicated in ALS, with the evidence supporting such a claim systematically reviewed
URL https://clinicalgenome.org/affiliation/40096/
 
Guideline Title Clingen Variant Curation Expert Panel for ALS
Description Expert member of Clingen Variant Curation Expert Panel on SOD1
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
URL https://clinicalgenome.org/affiliation/50096/
 
Guideline Title A proposal for new diagnostic criteria for ALS
Description Gold Coast Criteria for the Diagnosis of ALS
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact These are new diagnostic criteria for ALS and improve the way in which the diagnosis is given, simplify the route to making a diagnosis (therefore speeding it), improve access to clinical trials and clarify the diagnosis for patients, improving understanding.
URL https://www.sciencedirect.com/science/article/pii/S1388245720301383?via%3Dihub
 
Description Guidance on prevention strategies for ALS
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
 
Guideline Title Revised Airlie House consensus guidelines for design and implementation of ALS clinical trials
Description King's Clinical ALS Staging
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
Impact The clinical staging system is now recommended for ALS clinical trials, and is required by the FDA for future trials.
 
Guideline Title Revised Airlie House consensus guidelines for design and implementation of ALS clinical trials
Description King's clinical staging - in consensus guidelines for clinical trials in ALS
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in clinical guidelines
URL https://n.neurology.org/content/neurology/early/2019/03/08/WNL.0000000000007242.full.pdf
 
Description Standard operating procedure for King's ALS clinical staging
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact King's ALS clinical staging is now widely used in clinical practice and in clinical trials and other clinical research. This standard operating procedure ensures practice is uniform worldwide.
URL https://www.ncbi.nlm.nih.gov/pubmed/30773950
 
Description Timing of Riluzole use by clinical stage of ALS
Geographic Reach Multiple continents/international 
Policy Influence Type Influenced training of practitioners or researchers
Impact We showed that Riluzole extends the last stages of life with ALS. It has since also been shown that it extends the very early stages too by replicating our methods applied to a different dataset. These findings have impact on the advice given to patients, and mean that RIluzole should be started early, but also its use in late stage needs discussion with the patient, since it will simply extend life at a stage where health related quality of life is poor.
URL https://www.ncbi.nlm.nih.gov/pubmed/29525492
 
Description UK MND Translational Research Institute
Geographic Reach National 
Policy Influence Type Contribution to a national consultation/review
Impact Multiple institutions nationally have worked with four charities, several patients, and industry partners to produce a vision for motor neuron disease research nationally. The government agreed to fund our vision in full. A pilot proposal has been submitted and is in peer review. This brought together 6 institutions, 6 funders and 3 industry partners to accelerate research into a cure for motor neuron disease.
URL https://www.mndassociation.org/get-involved/campaigning/take-action/united-to-end-mnd/
 
Description A new strategy for clinical trials and personalised therapy in MND
Amount £119,768 (GBP)
Funding ID Al-Chalabi/Apr19/870-791 
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 07/2019 
End 07/2021
 
Description An Integrated Genome-Based Approach to Individualised Treatment in ALS and FTD
Amount $150,000 (USD)
Organisation The ALS Association 
Sector Charity/Non Profit
Country United States
Start 01/2022 
End 09/2023
 
Description Cognitive and behavioural impairment in Amyotrophic Lateral Sclerosis: Comparing measures and validating revised consensus diagnostic criteria for Amyotrophic Lateral Sclerosis - Frontotemporal Spectrum Disorder
Amount £95,574 (GBP)
Funding ID Goldstein/Oct17/892-792 
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2018 
End 09/2021
 
Description Deep Dementia Phenotyping and Diverse Precision Medicine
Amount £312,617 (GBP)
Organisation Alan Turing Institute 
Sector Academic/University
Country United Kingdom
Start 01/2022 
End 06/2022
 
Description Research Grant Studentship
Amount £95,574 (GBP)
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2018 
End 06/2021
 
Description Toward multiomics-based next-generation diagnostics for precision medicine in ALS and FTD
Amount £131,999 (GBP)
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2022 
End 07/2024
 
Description Using statistical models and machine learning to find subgroups of patients with homogeneous disease causes in Amyotrophic Lateral Sclerosis
Amount £166,384 (GBP)
Funding ID Iacoangeli/Apr19/869-791 
Organisation Motor Neurone Disease Association (MND) 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2019 
End 09/2025
 
Title DNA Scan v2 
Description DNA Scan v2 is a tool that allows automated annotation of human genome data quickly and efficiently, identifying SNVs, structural variants, indels, expansions and retroviruses automatically. 
Type Of Material Improvements to research infrastructure 
Year Produced 2021 
Provided To Others? Yes  
Impact The tool is being used to analyse genomics data from the MIROCALS phase 3 clinical trial 
URL https://github.com/hevmarriott/DNAscanv2
 
Title DNAscan: a fast, computationally and memory efficient bioinformatics pipeline for the analysis of DNA next-generation-sequencing data 
Description The generation of DNA Next Generation Sequencing (NGS) data is a commonly applied approach for studying the genetic basis of biological processes, including diseases, and underpins the aspirations of precision medicine. However, there are significant challenges when dealing with NGS data. A huge number of bioinformatics tools exist and it is therefore challenging to design an analysis pipeline; NGS analysis is computationally intensive, requiring expensive infrastructure which can be problematic given that many medical and research centres do not have adequate high performance computing facilities and the use of cloud computing facilities is not always possible due to privacy and ownership issues. We have therefore developed a fast and efficient bioinformatics pipeline that allows for the analysis of DNA sequencing data, while requiring little computational effort and memory usage. We achieved this by exploiting state-of-the-art bioinformatics tools. DNAscan can analyse raw, 40x whole genome NGS data in 8 hours, using as little as 8 threads and 16 Gbs of RAM, while guaranteeing a high performance. DNAscan can look for SNVs, small indels, SVs, repeat expansions and viral genetic material (or any other organism). Its results are annotated using a customisable variety of databases including ClinVar, Exac and dbSNP, and a local deployment of the gene.iobio platform is available for an on-the-fly result visualisation. 
Type Of Material Improvements to research infrastructure 
Year Produced 2018 
Provided To Others? Yes  
Impact The method speeded up our genetic research, overcoming computational and technical problems 
 
Title ENCALS Survival Model for ALS 
Description This mathematical tool allows a personalized survival prediction for patients. 
Type Of Material Improvements to research infrastructure 
Year Produced 2018 
Provided To Others? Yes  
Impact The tool allows a personalized survival prediction for any individual patient. This is used in clinic by neurologists to counsel patients, but is particularly useful for the design of clinical trials, and is now being used as an inclusion criterion in trials. 
URL http://encalssurvivalmodel.org/
 
Title Penetrance Calculator Tool 
Description This is a tool to estimate gene penetrance (the probability of phenotype given genotype) from a number of potential parameters that might be available when family data is missing. For example, the rate of sporadic disease and familial disease can be used to estimate penetrance. 
Type Of Material Improvements to research infrastructure 
Year Produced 2021 
Provided To Others? Yes  
Impact The tool has been used to estimate penetrance of a number of ALS genes which is of importance for genetic counselling. We are developing the tool further to allow age-dependent analyses. 
URL https://adpenetrance.rosalind.kcl.ac.uk/
 
Title Retrosnake 
Description This is a research tool to identify retrovirus or transposable element sequences in human genomic data. 
Type Of Material Improvements to research infrastructure 
Year Produced 2021 
Provided To Others? No  
Impact The tool has been used to inform the NIHR-funded phase 3 clinical trial Lighthouse 2. The link is set to private pending approval to make public from a collaborating partner. 
URL https://github.com/KHP-Informatics/RetroSnake
 
Title Standard Operating Procedure for King's ALS Clinical Staging 
Description Clinical staging method for people with ALS. The King's system is now widely used internationally in clinic, research and clinical trials. 
Type Of Material Physiological assessment or outcome measure 
Year Produced 2019 
Provided To Others? Yes  
Impact Clinical trial design now incorporates King's staging to understand the timing of treatment benefit, for analysis as an outcome measure, and for health economics analysis. 
URL https://www.ncbi.nlm.nih.gov/pubmed/30773950
 
Title ALSoD 
Description The ALS Online Database is a genetic database showing all ALS related genetic variations with their evidence and various tools for understanding phenotype, penetrance, publications and credibility. 
Type Of Material Database/Collection of data 
Provided To Others? Yes  
Impact Currently, data from this database is being used to inform commercial gene therapy studies in ALS. It is also widely accessed internationally and therefore used in multiple research projects. 
URL http://www.alsod.ac.uk
 
Title Drugtargetor: Genetics-driven drug-target networks 
Description The Work Package 3 Team from King's College London has developed drugtargetor.com which harnesses results from genome-wide association studies (GWAS), and drug bioactivity data, to prioritize drugs and targets for a given phenotype. Drug Targetor networks are constructed using genetically scored drugs and genes, connected by the type of drug-target or drug-gene interaction. 
Type Of Material Computer model/algorithm 
Year Produced 2018 
Provided To Others? Yes  
Impact GWAS and drug targets: We have performed detailed analyses of every BRAIN MEND phenotype with genome-wide association study data and over 600 other traits across medicine. The results are available at drugtargetor.com. This focusses on common genetic variants. Many of the disorders have known rare mutations and we are proceeding to make lists of mutations for each disorder, and in this way will be able to include the rarer BRAIN-MEND phenotypes. 
URL http://www.drugtargetor.com/
 
Title Navigome: Phenome navigator Lipid correlation with ALS 
Description In the navigome.com website the Work Package 3 Team from King's College London has built a framework to integrate imputed gene-expression for any phenotype with GWAS data. They plan to integrate the brain expression data from the BRAIN-MEND partners and make private consortium specific versions of the website so that the new data can be analysed and explored prior to publication (including the analyses from Work Package 1). 
Type Of Material Computer model/algorithm 
Year Produced 2018 
Provided To Others? Yes  
Impact - Browse pathways, gene and tissue analyses, using interactive visualizations - Generate gene profiles across phenotypes and tissues 
URL https://phenviz.navigome.com/
 
Title Survival prediction model for ALS 
Description A comprehensive survival prediction tool for ALS 
Type Of Material Computer model/algorithm 
Year Produced 2018 
Provided To Others? Yes  
Impact Use of the model by pharmaceutical company analyzing clinical trial data 
URL http://encalssurvivalmodel.org/
 
Description BRAIN-MEND 
Organisation EU Joint Programme - Neurodegenerative Disease Research (JPND)
Country European Union (EU) 
Sector Public 
PI Contribution Coordinator. Samples, expertise, data, infrastructure
Collaborator Contribution Samples, expertise, data, infrastructure
Impact None yet
Start Year 2018
 
Description Precision ALS 
Organisation University College Dublin
Country Ireland 
Sector Academic/University 
PI Contribution We are contributing clinical data from a population register of ALS
Collaborator Contribution A large data handling and storage infrastructure, able to link multiple forms of data internationally
Impact None yet
Start Year 2022
 
Description Project MinE 
Organisation Trinity College Dublin
Department Neurology
Country Ireland 
Sector Academic/University 
PI Contribution This is an international whole genome sequencing consortium possible because of the infrastructure derived from the MRC/JPND programme STRENGTH - we have contributed 2000 ALS and control samples as well as funding and a template for other teams to obtain funding
Collaborator Contribution The partners have contributed whole genome sequences and negotiated with us for infrastructure. See http://www.projectmine.com
Impact Various genetics papers listed under STRENGTH programme
Start Year 2014
 
Description Project MinE 
Organisation University Medical Center Utrecht (UMC)
Country Netherlands 
Sector Academic/University 
PI Contribution This is an international whole genome sequencing consortium possible because of the infrastructure derived from the MRC/JPND programme STRENGTH - we have contributed 2000 ALS and control samples as well as funding and a template for other teams to obtain funding
Collaborator Contribution The partners have contributed whole genome sequences and negotiated with us for infrastructure. See http://www.projectmine.com
Impact Various genetics papers listed under STRENGTH programme
Start Year 2014
 
Description Project MinE 
Organisation University of Massachusetts
Department University of Massachusetts Medical School
Country United States 
Sector Academic/University 
PI Contribution This is an international whole genome sequencing consortium possible because of the infrastructure derived from the MRC/JPND programme STRENGTH - we have contributed 2000 ALS and control samples as well as funding and a template for other teams to obtain funding
Collaborator Contribution The partners have contributed whole genome sequences and negotiated with us for infrastructure. See http://www.projectmine.com
Impact Various genetics papers listed under STRENGTH programme
Start Year 2014
 
Description TONiC genetics study 
Organisation The Walton Centre
Country United Kingdom 
Sector Hospitals 
PI Contribution We are combining national register data with genetics and proteomics data and the TONiC study to add value to each study.
Collaborator Contribution We are contributing the register infrastructure and genetics remote sampling know-how.
Impact None yet
Start Year 2021
 
Description UK MND Research Institute 
Organisation MND Scotland
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution I am the scientific lead for a national programme for MND research. The collaboration was to ask government for £50M for MND research over 5 years, with matched industry and charity funding. A government announcement was made confirming we were successful in September.
Collaborator Contribution This has been a team effort, with fortnightly meetings for two years.
Impact AS a result of this campaign, public knowledge of MND is far greater than before. We achieved a parliamentary debate, repeated national news coverage (which continues), policy change from government, policy change from the Welsh Senedd in progress, meetings with government ministers and advisers, and a pledge of funding from government.
Start Year 2020
 
Description UK MND Research Institute 
Organisation Motor Neurone Disease Association (MND)
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution I am the scientific lead for a national programme for MND research. The collaboration was to ask government for £50M for MND research over 5 years, with matched industry and charity funding. A government announcement was made confirming we were successful in September.
Collaborator Contribution This has been a team effort, with fortnightly meetings for two years.
Impact AS a result of this campaign, public knowledge of MND is far greater than before. We achieved a parliamentary debate, repeated national news coverage (which continues), policy change from government, policy change from the Welsh Senedd in progress, meetings with government ministers and advisers, and a pledge of funding from government.
Start Year 2020
 
Description UK MND Research Institute 
Organisation My Name'5 Doddie Foundation
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution I am the scientific lead for a national programme for MND research. The collaboration was to ask government for £50M for MND research over 5 years, with matched industry and charity funding. A government announcement was made confirming we were successful in September.
Collaborator Contribution This has been a team effort, with fortnightly meetings for two years.
Impact AS a result of this campaign, public knowledge of MND is far greater than before. We achieved a parliamentary debate, repeated national news coverage (which continues), policy change from government, policy change from the Welsh Senedd in progress, meetings with government ministers and advisers, and a pledge of funding from government.
Start Year 2020
 
Description UK MND Research Institute 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution I am the scientific lead for a national programme for MND research. The collaboration was to ask government for £50M for MND research over 5 years, with matched industry and charity funding. A government announcement was made confirming we were successful in September.
Collaborator Contribution This has been a team effort, with fortnightly meetings for two years.
Impact AS a result of this campaign, public knowledge of MND is far greater than before. We achieved a parliamentary debate, repeated national news coverage (which continues), policy change from government, policy change from the Welsh Senedd in progress, meetings with government ministers and advisers, and a pledge of funding from government.
Start Year 2020
 
Description UK MND Research Institute 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution I am the scientific lead for a national programme for MND research. The collaboration was to ask government for £50M for MND research over 5 years, with matched industry and charity funding. A government announcement was made confirming we were successful in September.
Collaborator Contribution This has been a team effort, with fortnightly meetings for two years.
Impact AS a result of this campaign, public knowledge of MND is far greater than before. We achieved a parliamentary debate, repeated national news coverage (which continues), policy change from government, policy change from the Welsh Senedd in progress, meetings with government ministers and advisers, and a pledge of funding from government.
Start Year 2020
 
Description UK MND Research Institute 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution I am the scientific lead for a national programme for MND research. The collaboration was to ask government for £50M for MND research over 5 years, with matched industry and charity funding. A government announcement was made confirming we were successful in September.
Collaborator Contribution This has been a team effort, with fortnightly meetings for two years.
Impact AS a result of this campaign, public knowledge of MND is far greater than before. We achieved a parliamentary debate, repeated national news coverage (which continues), policy change from government, policy change from the Welsh Senedd in progress, meetings with government ministers and advisers, and a pledge of funding from government.
Start Year 2020
 
Description UK MND Research Institute 
Organisation University of Sheffield
Country United Kingdom 
Sector Academic/University 
PI Contribution I am the scientific lead for a national programme for MND research. The collaboration was to ask government for £50M for MND research over 5 years, with matched industry and charity funding. A government announcement was made confirming we were successful in September.
Collaborator Contribution This has been a team effort, with fortnightly meetings for two years.
Impact AS a result of this campaign, public knowledge of MND is far greater than before. We achieved a parliamentary debate, repeated national news coverage (which continues), policy change from government, policy change from the Welsh Senedd in progress, meetings with government ministers and advisers, and a pledge of funding from government.
Start Year 2020
 
Description United2EndMND Research Group 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution I am the scientific lead for a national campaign for funding MND Research over 5 years through a national programme of research. With colleagues, I have successfully lobbied for funding. We have developed a scientific vision for the programme. An initial pilot scheme using £4.25M is described here.
Collaborator Contribution Colleagues have helped develop the vision and written the programme of work, leading various work packages.
Impact None yet
Start Year 2021
 
Description United2EndMND Research Group 
Organisation University of Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution I am the scientific lead for a national campaign for funding MND Research over 5 years through a national programme of research. With colleagues, I have successfully lobbied for funding. We have developed a scientific vision for the programme. An initial pilot scheme using £4.25M is described here.
Collaborator Contribution Colleagues have helped develop the vision and written the programme of work, leading various work packages.
Impact None yet
Start Year 2021
 
Description United2EndMND Research Group 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution I am the scientific lead for a national campaign for funding MND Research over 5 years through a national programme of research. With colleagues, I have successfully lobbied for funding. We have developed a scientific vision for the programme. An initial pilot scheme using £4.25M is described here.
Collaborator Contribution Colleagues have helped develop the vision and written the programme of work, leading various work packages.
Impact None yet
Start Year 2021
 
Description United2EndMND Research Group 
Organisation University of Sheffield
Country United Kingdom 
Sector Academic/University 
PI Contribution I am the scientific lead for a national campaign for funding MND Research over 5 years through a national programme of research. With colleagues, I have successfully lobbied for funding. We have developed a scientific vision for the programme. An initial pilot scheme using £4.25M is described here.
Collaborator Contribution Colleagues have helped develop the vision and written the programme of work, leading various work packages.
Impact None yet
Start Year 2021
 
Title Use of CSF-Neurofilament determinations and CSF-Neurofilament thresholds of prognostic and stratification value with regards to response to therapy in neuromuscular and neurodegenerative diseases. 
Description A method to stratify patients by predicted response to therapy 
IP Reference  
Protection Patent / Patent application
Year Protection Granted
Licensed Commercial In Confidence
Impact Stratifying patients for treatment response
 
Title Lighthouse Trial 
Description Phase 2 trial of Triumeq in ALS now complete and published. Seeking Phase 3 start. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2019
Development Status Actively seeking support
Clinical Trial? Yes
Impact Increased collaboration internationally on ALS clinical trials 
URL https://www.tandfonline.com/doi/full/10.1080/21678421.2019.1632899
 
Title Lithium PRELUDE trial 
Description We have shown that Lithium carbonate, while ineffective in ALS as a whole, is effective in people with a poor prognosis genetic variant in the UNC13A gene (homozygosity for the CC genotype). We are now seeking funding for a trial of lithium in patients with ALS who carry this poor prognosis variant. This will be a precision medicine approach in ALS. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2019
Development Status Actively seeking support
Impact The initial findings have been published, and if the trial confirms the analysis, this will become a new treatment for ALS. 
URL https://www.ncbi.nlm.nih.gov/pubmed/28978660
 
Title MIROCALS 
Description A clinical trial of low-dose interleukin-2 for amyotrophic lateral sclerosis, currently in a Phase 2 clinical trial, funded by Horizon 2020 and the MND Association 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2015
Development Status Under active development/distribution
Impact The trial includes an assessment of Riluzole therapy, the first of its kind 
URL http://www.mirocals.eu/en/
 
Title Trial of Triumeq in ALS 
Description Triumeq is an antiretroviral combination drug used for HIV infection. We have shown in repeated studies, independently confirmed by others, that a generic signature of retroviral infection is present in the blood of people with ALS, and that this is likely to be from an endogenous retrovirus. A possible causative retrovirus was recently identified as HERV-K. Triumeq is 100 times more effective against HERV-K than against HIV. We are therefore actively seeking funding for a trial of Triumeq in ALS. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2019
Development Status Actively seeking support
Impact None yet 
 
Title ALSgenScanner 
Description ALSgeneScanner is a tool to allow neurologists to analyze whole genome sequence data for mutations specific to ALS and generates a detailed annotated report for each patient. 
Type Of Technology Software 
Year Produced 2019 
Open Source License? Yes  
Impact It has only just been released, but has had a good reception on social media platforms (Twitter in particular). 
URL https://www.tandfonline.com/doi/full/10.1080/21678421.2018.1562553
 
Title DNAscan 
Description A fast, computationally and memory efficient bioinformatics pipeline for the analysis of DNA next-generation-sequencing data 
Type Of Technology Software 
Year Produced 2018 
Open Source License? Yes  
Impact Improved analysis pipeline for the international Project MinE whole genome sequencing consortium (http://www.projectmine.com) 
URL https://www.biorxiv.org/content/early/2018/02/18/267195
 
Title Survival model for ALS 
Description A tool for predicting survival in ALS 
Type Of Technology Webtool/Application 
Year Produced 2018 
Impact Use of the prediction tool for analysis of clinical trial phase 2 data 
URL http://www.encalssurvivalmodel.org
 
Description ALS Debate 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Debate on Genetics vs Environment in ALS
Year(s) Of Engagement Activity 2019
URL https://www.alsmndinnovation.com/Home/Event/6
 
Description Addressing the All Party Parliamentary Group on MND 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Presentation to the APPG on MND regarding our campaign for a step change in the quantity and nature of research funding for MND. Presented on 3 occasions. Attended by multiple politicians on each occasion. As a result, parliamentary questions were asked on our behalf and government policy was changed.
Year(s) Of Engagement Activity 2021,2022
URL https://www.mndassociation.org/get-involved/campaigning/take-action/united-to-end-mnd/
 
Description Addressing the All Party Parliamentary Group on MND 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Spoke on MND research at the APPG on MND in December 2022
Year(s) Of Engagement Activity 2022
 
Description BRAIN-MEND twitter account 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact BRAIN-MEND has a Twitter account which was launched at the International ALS Symposium in Glasgow in December 2018 and will be used to disseminate research findings to academics and the general public.
Year(s) Of Engagement Activity 2018
 
Description JNNP Podcast 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I was interviewed for a podcast about our recent finding that genetic variants that increase ALS risk, also lower the age of onset. Our paper was Editor's Choice.
Year(s) Of Engagement Activity 2019
 
Description Kick-Off Meeting AUSTRALIA, 23 March 2018, Melbourne, Australia 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Study participants or study members
Results and Impact Prof Ammar Al-Chalabi and Prof Jan Veldink represented the BRAIN-MEND Consortium to meet up with the Australian partners at the International Symposium on ALS/MND to discuss the governance of the project and plan for 2018.
Year(s) Of Engagement Activity 2018
 
Description Kick-Off Meeting EUROPE, 25 May 2018, London, UK 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Study participants or study members
Results and Impact After the official start of the project, the Project Coordinator organised the BRAIN-MEND Kick-Off meeting for the European partners of project BRAIN-MEND which took place at King's College London, UK on 25 May 2018. All Consortium members were present and each WP leader presented their plan for respective Work Package.
Year(s) Of Engagement Activity 2018
 
Description Lecture tour for researchers, patients and clinicians to South America 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact Lectures and Question and Answer sessions were held at several locations in Uruguay and Argentina, including a university in Montevideo, 3 universities in Buenos Aires region, and a hotel in Buenos Aires city. The sessions included simultaneous translation Spanish and English and were live streamed on Facebook, as well as remaining available now. The question and answer session was with patients and carers, and lasted nearly two hours. The entire trip was coordinated by the ELA Association, a South American ALS association, which is now affiliated with the international alliance of ALS/MND Associations.
Year(s) Of Engagement Activity 2018
URL http://www.asociacionela.org.ar/index.php/pregunta-a-los-expertos-1
 
Description MND Connect 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact Patient-researcher-clinician question and answer session also live-streamed
Year(s) Of Engagement Activity 2019
URL https://www.youtube.com/watch?v=KRb1HWv08gQ
 
Description MNDA Legacy Event 2019 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Tour of labs and clinics with talks by researchers and clinicians
Year(s) Of Engagement Activity 2019
 
Description MNDA Legacy Event September 2018 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Supporters
Results and Impact The event was to educate the general public and those engaged with the MND Association about the research done that is funded by the MNDA, with the aim of increasing knowledge and encouraging a legacy to such research,
Year(s) Of Engagement Activity 2018
 
Description Media campaign over months for an MND Translational Research Institute 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact An orchestrated campaign with multiple interviews on BBC Breakfast (three interviews), BBC radio channels, and the Sunday Express (was the Express campaign for several months, until success). The campaign was to influence government policy on research into motor neuron disease. Government agreed to fund a £50m 5 year vision for coordinated MND research nationally. The campaign has also been seen and copied in other countries and was described by Business Secretary Kwasi Kwarteng, as "a textbook parliamentary campaign". An example URL is given below but many exist.
Year(s) Of Engagement Activity 2020,2021,2022
URL https://twitter.com/BBCBreakfast/status/1330796880888999938
 
Description Ministerial Roundtable on MND 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact A ministerial roundtable on MND to discuss how to continue funding for the UK MND Research Institute
Year(s) Of Engagement Activity 2023
 
Description Ministerial Roundtable on MND 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact This was a ministerial roundtable on MND convened by NIHR as a result of a parliamentary debate, itself a result of a petition and media campaign to improve MND research to a cure.
Year(s) Of Engagement Activity 2021
 
Description NIHR MND Engage 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact A study day on PPI
Year(s) Of Engagement Activity 2019
 
Description New Zealand Inaugural MND Talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Patients, carers and/or patient groups
Results and Impact I gave the plenary talk at the inaugural MND New Zealand research symposium which sparked multiple questions and disussions
Year(s) Of Engagement Activity 2019
URL https://anzasw.nz/events/motor-neuron-disease-mnd-new-zealand-research-conference-2019/
 
Description Parliamentary Debate on MND Research 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact On 12 July 2021, a parliamentary debate was held on our vision for a UK MND Translational Research Institute. This was a vision initially started by two patients with me, and developed by a coalition of patients, patient charities, scientists and industry partners. The debate was one component of a campaign which led to agreed government funding of £50m over 5 years.
Year(s) Of Engagement Activity 2021
URL https://www.youtube.com/watch?v=SgE1JfFrl20
 
Description Poster at ENCALS 2019, Tours, France 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A poster entitled "Plasma neurofilament light chain for the diagnosis of neurdegenerative diseases" was presented by Dr Ahmad Al Khleifat et al in the European ALS Conference ENCALS which took place from 15 - 17 May in Tours, France.
Year(s) Of Engagement Activity 2019
URL https://www.encals.eu/meetings/encals-meeting-2019-tours-france/
 
Description Scientific Advisory Board and Workshop for Platform Trials at the MGH Healey Center 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Current clinical trials are performed sequentially in ALS, which is a very slow method for a devastating fatal disease. Platform trials offer a perpetual trial design, with 3:1 active to placebo participation, and multiple simultaneous trials, greatly accelerating drug discovery and improving patient participation. This board and series of workshops aims to make such trials a reality in ALS.
Year(s) Of Engagement Activity 2018,2019
 
Description Second Consortium Meeting, 06 December 2018, Glasgow, Scotland 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Study participants or study members
Results and Impact The second consortium meeting took place in Glasgow on 06 December 2018 at the International ALS Symposium. All project partners were represented. Updates on progress were heard from the various work package leaders and future plans were discussed. Project partners also discussed and agreed on a continued good strategic planning of next 12 months including regular WP team conference calls and internal meetings for UK partners.
Year(s) Of Engagement Activity 2018
 
Description Teleconference with the Work Package 2 Team 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Study participants or study members
Results and Impact Team members from King's College London held a teleconference with WP2 members from the University of Queensland to update each other on the progress made within WP2 and discuss the next milestones for 2019.
Year(s) Of Engagement Activity 2018
 
Description Teleconference with the Work Package 4 Team 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Study participants or study members
Results and Impact Team members from King's College London held a teleconference with WP4 members from the Trinity College Dublin to update each other on the progress made within WP4, and discuss the collaboration with colleagues from the School of Computer Science in Trinity College. Number of productive meetings with the English and Irish teams took place to discuss the plans for WP4 works in 2019.
Year(s) Of Engagement Activity 2018
 
Description Visit by the Secretary of State for Health and Social Care 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact The SoS for Health and Social Care, Steve Barclay, visited our are and research centre, had a 15 minute private meeting with us, and interacted with staff, research students and media.
Year(s) Of Engagement Activity 2023
URL https://www.kcl.ac.uk/news/secretary-of-state-for-health-and-social-care-visits-kings-college-london