UKDP: Integrated DEmentiA research environment (IDEA)

Lead Research Organisation: University College London
Department Name: Institute of Neurology

Abstract

The UK Dementias Platform (UKDP) is a radically new approach to dementias research. It brings together data from
around 2,000,000 study participants from 22 cohorts to try and discover the causes of dementia and to find out ways of
slowing it down. The platform has been funded to the level of £12M.
In this proposal we want to improve UK infrastructure for dementia research so that the most can be made of the
opportunity provided by UKDP. We wan to improve the infrastructure by buying important pieces of equipment that will put
the UK at the forefront of dementia research worldwide and by establishing networks of scientists who will work together to
make best use of the equipment.
The three themes of the proposal are imaging, informatics and stem cells.
For imaging we want to establish a network of PET/MR scanning facilities across the UK so that the molecular processes
going on inside the brain that cause dementia can be studied.
For informatics we want to be bring together bas many different types of data as possible and make it easy as possible for
scientists to use them
For stem cells we want to take cells form adults with and without dementia to find out how cells change as the dementias
process begins and progresses.
We believe these proposals will raise standards, reduce costs, and deliver innovative and coordinated research, making
the UK an internationally unique place to study dementia.

Technical Summary

Our objective is to achieve a step-change in UK dementia research capacity through establishing national networks of
existing and emerging centres of excellence in imaging, informatics and cell-biology.
The UK Dementias Platform (UKDP) is a radically new approach to dementias research, providing a highly efficient and
cost-effective translational pipeline from discovery through to early phase trials. UKDP will create closer synergy between
epidemiology and experimental medicine with the re-purposing of epidemiologic cohorts for trials readiness. The size and
depth of phenotyping available to UKDP will deliver a step-change in the complexity and granularity of dementia related
hypothesis testing and accelerate compound development.
Proposed here is an infrastructure of investment and collaboration. Underpinning UKDP is a critical mass of researchers
and resources that will work together to encourage, facilitate, and develop a fully integrated dementia dedicated UK
research environment. This will raise standards, reduce costs, and deliver innovative and coordinated research, to make
the UK an internationally unique research environment. Through its partnership with major academic centres and industry,
UKDP is well positioned to achieve this goal.
Building on the recent MRC investment in UKDP, we propose here to renew and extend the UKDP integrative research
environment with an advanced molecular imaging network strategically located to exploit UKDP cohorts. Also proposed is
an integrated informatics environment to facilitate the location of and access to both data and bio-samples. The third
proposal is for a stem-cells network to promote the use of this important and emerging technology. Each of these elements
adds value to existing infrastructure investments and fills significant gaps in the UK research landscape.

Planned Impact

The current proposal in in support of the UKDP and will become part of the the UKDP impact strategy.
In summary, the UKDP strategy to deliver pact is to develop networks of partnership to actively consult engage the UK
academic community in relation to dementia research focussing on the direction,
technologies and collaborations of the UKDP and the wider UK national infrastructure.
Our aim is to:

1) promote the best possible science
2) create momentum in dementias research by being inclusive of, and synergistic with, other initiatives.
Partnership discussions with industry are already underway with exchanges of ides, interests and needs between
academic and industry stakeholders. Industry have identified their need for access to conversion (early MVI to dementia
cohorts and for experimental medicine studies to conform to regulatory requirements.
We remain committed to raising the profile of contemporary debate about dementia and its treatment. We wish to
encourage a culture of commitment to solving this problem. By increasing awareness at all levels of society we intend to
leverage resources for the platform and for dementia research in general, to increase awareness of the need for earlier
interventions and better targeted treatment in general by health service providers and the public alike.
Engagement with the general public and with patients and carers is a very important part of our mission. This serves not
only to communicate our research findings and their relevance but also to address such issues as stigma in society and the
research culture in the NHS in relation to dementia and older people. In addition to using the platform web-site to
communicate to the general public, we will also liaise with charities and advocate groups such as Age UK and the
Alzheimer's Society to promote our work and findings and to engage them in shaping the work programme.
In addition we will have a dedicated free-phone number available 6 days a week and a communications officer at 50% FTE
over 5 years whose responsibility is to develop and implement a communications and public engagement strategy.

Publications

10 25 50
 
Description Member of expert panel advising the Dementia Discovery Fund for potential investments in autophagy research
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
 
Description EU Innovative Medicines Initiative
Amount € 900,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 06/2016 
End 05/2021
 
Description High Content Screening (HCS) platform for HD drug discovery
Amount £381,185 (GBP)
Organisation Takeda Pharmaceutical Company 
Sector Private
Country Global
Start 12/2017 
End 12/2019
 
Description Investigating proteostasis in development and disease using iPSC neurons with MAPT mutations linked to FTD
Amount £107,034 (GBP)
Funding ID BB/S506886/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2018 
End 09/2022
 
Description Lysosome turnover in health, aging and disease
Amount £1,232,805 (GBP)
Funding ID 212216/Z/18/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2019 
End 05/2024
 
Description MRC Partnership Grant
Amount £1,220,774 (GBP)
Funding ID MR/N013255/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 06/2016 
End 05/2019
 
Description Molecular Characterization of FAN1 Variation in Huntington's disease
Amount £163,169 (GBP)
Organisation CHDI Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2017 
End 06/2018
 
Description Non cell autonomous Alzheimer's disease in iPSC derived cells - astrocyte reactivity and APP signalling
Amount £224,932 (GBP)
Funding ID 177986 
Organisation Alzheimer’s Society 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2018 
End 02/2022
 
Description Research Grant
Amount £204,308 (GBP)
Organisation CBD Solutions 
Sector Private
Country Unknown
Start 07/2018 
End 12/2019
 
Description Senior Research Fellowship
Amount £420,000 (GBP)
Funding ID ARUK-SRF2016B-2 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2017 
End 03/2022
 
Description TDRF
Amount £151,213 (GBP)
Funding ID BB/P027431/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2018 
End 02/2019
 
Description UCL Eisai collaboration
Amount £5,000,000 (GBP)
Organisation Eisai Ltd 
Sector Private
Country Japan
Start 11/2017 
End 04/2019
 
Description UCL RCIF Capital Equipment Fund 2018-19
Amount £155,000 (GBP)
Organisation University College London 
Sector Academic/University
Country United Kingdom
Start 09/2018 
 
Description UCL-Eisai Therapeutic Innovation Group: - Eisai Ltd: - UCL-Eisai Therapeutic Innovation Group (£ 60000; 2018 - 2019)
Amount £60,000 (GBP)
Funding ID 522585 
Organisation Eisai Ltd 
Sector Private
Country Japan
Start 08/2018 
End 09/2019
 
Description University of Pennsylvania Orphan Disease Center
Amount $51,020 (USD)
Funding ID MDBR-19-102-BPAN 
Organisation University of Pennsylvania 
Sector Academic/University
Country United States
Start 02/2019 
End 01/2020
 
Description WT Institutional Strategic Support Fund
Amount £65,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2015 
End 12/2017
 
Title AAV Vectors for CNS expression 
Description Investigation of the therapeutic potential of reduction of tau protein in CNS using truncated long non-coding RNA linked to the tau gene. Derivation of AAV9 vectors for CNS delivery of the long non-coding RNAs 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2018 
Provided To Others? No  
Impact Project in progress. Current outcome: Wide CNS distribution after AAV9 injection in mouse model with reduction in brain levels of tau. We expect accompanying therapeutic effect. 
 
Title Cellular FRET biosensor for tau aggregation 
Description This is a cellular model with co-expression of GFP- and RFP-tau and is a robust model to study tau aggregation and assess the therapeutic potential of anti-aggregation agents and antibodies 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2018 
Provided To Others? No  
Impact With this robust biosensor, we have shown the potential therapeutic anti-aggregation potential of anti-tau antibodies that we have developed. 
 
Title Stable cell lines for tau gene associated non-coding RNA genes 
Description Stable overexpression of non-coding RNA genes enables consistent cell-based model to investigate the downstream regulatory effects of these non-coding genes 
Type Of Material Model of mechanisms or symptoms - in vitro 
Year Produced 2015 
Provided To Others? No  
Impact Have succeeded in clarifying the precise role of the non-coding RNA genes in the post-transcriptional regulation of tau gene expression 
 
Description ARUK DDI 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution The UKDP is working closely with the ARUK Drug Discovery Institute with the aim to develop novel therapies for neurodegenerative disorders. Both networks collaborate closely in terms of drug discovery research and through exchange of knowledge, equipment and technologies.
Collaborator Contribution The UKDP is working closely with the ARUK Drug Discovery Institute with the aim to develop novel therapies for neurodegenerative disorders. Both networks collaborate closely in terms of drug discovery research and through exchange of knowledge, equipment and technologies.
Impact None yet
Start Year 2017
 
Description CBD clinicopathological classification 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Part of team to investigate clinico-pathological correlates in progression of corticobasal degeneration and pathological seeding species. Participating with expert input into project and assisting in experimental procedures.
Collaborator Contribution They have described markers of clinico-pathological progression of tauopathy in corticobasal degeneration (CBD) and obtained funding for neuropathological classification of CBD sub-types and established methodology to investigate pathological seeding and spread in postmortem material.
Impact Ongoing.
Start Year 2017
 
Description Dementia Platform UK Stem Cell Network 
Organisation Cardiff University
Department School of Biosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Developed a strategy for integrating stem cell neuronal research across 6 centres for harmonising and validating protocols, high content imaging of models, neurophysiology, genomics and proteomics,
Collaborator Contribution As above
Impact Two teaching technical workshops held at Oxford and Cambridge.
Start Year 2015
 
Description Dementia Platform UK Stem Cell Network 
Organisation University of Cambridge
Department Gurdon Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Developed a strategy for integrating stem cell neuronal research across 6 centres for harmonising and validating protocols, high content imaging of models, neurophysiology, genomics and proteomics,
Collaborator Contribution As above
Impact Two teaching technical workshops held at Oxford and Cambridge.
Start Year 2015
 
Description Dementia Platform UK Stem Cell Network 
Organisation University of Edinburgh
Department Centre for Clinical Brain Sciences (CCBS)
Country United Kingdom 
Sector Academic/University 
PI Contribution Developed a strategy for integrating stem cell neuronal research across 6 centres for harmonising and validating protocols, high content imaging of models, neurophysiology, genomics and proteomics,
Collaborator Contribution As above
Impact Two teaching technical workshops held at Oxford and Cambridge.
Start Year 2015
 
Description Dementia Platform UK Stem Cell Network 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution Developed a strategy for integrating stem cell neuronal research across 6 centres for harmonising and validating protocols, high content imaging of models, neurophysiology, genomics and proteomics,
Collaborator Contribution As above
Impact Two teaching technical workshops held at Oxford and Cambridge.
Start Year 2015
 
Description Dementia Platform UK Stem Cell Network 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Developed a strategy for integrating stem cell neuronal research across 6 centres for harmonising and validating protocols, high content imaging of models, neurophysiology, genomics and proteomics,
Collaborator Contribution As above
Impact Two teaching technical workshops held at Oxford and Cambridge.
Start Year 2015
 
Description Gamma secretase stabilisiers 
Organisation Janssen Pharmaceutica NV
Country Belgium 
Sector Private 
PI Contribution Establishment of a high throughput screen to identify compounds that modulate gamma secretase enzyme activity.
Collaborator Contribution Supply of reagents (antibodies) and compound libraries
Impact The compound screen is currently being run. We hope to identify novel compounds to enable a drug discovery programme
Start Year 2018
 
Description Mitophagy 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Establishment of a phenotypic assay to enable identification of novel pathways for mitophagy in Parkinsons disease
Collaborator Contribution Helen Plun Favreau. Deep knowledge of Parkinsons disease and mitophagy biology. Follow up biological validation of hits identified in the siRNA screen.
Impact a publication is being prepared
Start Year 2017
 
Description Notum inhibitors 
Organisation Francis Crick Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Identification of small molecule inhibitors of the Wnt signaling inhibitor enzyme Notum
Collaborator Contribution Oxford - X ray crystal structure of Notum to enable the drug discovery Crick - generation of genetically modified mice for understanding of the functional rolel of notum
Impact Papers: Fish PV, Steadman, D, Bayle ED, Whiting PJ (2019). New Approaches for the Treatment of Alzheimer's Disease. Bioorg. Med. Chem Lett. 29: 125-131 Atkinson BN, Steadman D, Zhao, Sipthorp J, Vecchia L, Ruza RR, Jeganathan F, Lines G, Frew S, Monaghan A, Kjaer S, Bictash M, Jones EY, Fish PV. Discovery of 2-phenoxyacetamides as Inhibitors of the Wnt-depalmitoleating enzyme NOTUM from an X-ray Fragment Screen. Med. Chem. Comm. Submitted February 2019.
Start Year 2017
 
Description Notum inhibitors 
Organisation University of Oxford
Country United Kingdom 
Sector Academic/University 
PI Contribution Identification of small molecule inhibitors of the Wnt signaling inhibitor enzyme Notum
Collaborator Contribution Oxford - X ray crystal structure of Notum to enable the drug discovery Crick - generation of genetically modified mice for understanding of the functional rolel of notum
Impact Papers: Fish PV, Steadman, D, Bayle ED, Whiting PJ (2019). New Approaches for the Treatment of Alzheimer's Disease. Bioorg. Med. Chem Lett. 29: 125-131 Atkinson BN, Steadman D, Zhao, Sipthorp J, Vecchia L, Ruza RR, Jeganathan F, Lines G, Frew S, Monaghan A, Kjaer S, Bictash M, Jones EY, Fish PV. Discovery of 2-phenoxyacetamides as Inhibitors of the Wnt-depalmitoleating enzyme NOTUM from an X-ray Fragment Screen. Med. Chem. Comm. Submitted February 2019.
Start Year 2017
 
Description PerkinElmer 
Organisation Perkin Elmer
Country United States 
Sector Private 
PI Contribution Closely working together on the development of high-content screening technologies. We provide expertise and knowledge.
Collaborator Contribution We have received free hardware and software upgrades, e.g. free 5x objective and software upgrades.
Impact This has enabled the use of additional technologies on the platform, e.g. Presiscan, FRET.
Start Year 2017
 
Description Simon-Raj In vivo work 
Organisation University College London
Department Institute for Women's Health
Country United Kingdom 
Sector Academic/University 
PI Contribution Indentification and characterisation of tau gene promoter associated long-non-coding RNA gene involved in regulation of tau gene. Design of active minimised variants and derivation of AAV expression vectors for in vivo work
Collaborator Contribution Maintenance of mouse colony, AAV injection and behavioural studies
Impact Ongoing. One publication has resulted from collaboration (PMID: 30081233)
Start Year 2016
 
Description Tau-based gene therapy for neurodegenerative disorders 
Organisation Karolinska University Hospital
Department Center for Molecular Medicine
Country Sweden 
Sector Hospitals 
PI Contribution We have developed vectors to test the concept of gene therapy directed at tau gene expression in slowing or halting the progress of tau-relaed neurodegeneration.
Collaborator Contribution Injection and study of mouse models for tauopathy
Impact None to date - still in progress
Start Year 2015
 
Title E2814 anti-tau Clinical Trial 
Description Therapeutic intervention Phase I clinical trials for Alzheimer's disease to commence in April 2019 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2019
Development Status Under active development/distribution
Impact Still under assessment 
 
Title lncRNAs and therapeutic reduction of tau 
Description Refined/truncated lncRNA transcript delivery in vivo by AAV vectors to test if tau is reduced and if there is any therapeutic benefits in animal models of tauopathies. Most recent funding from Brain Research Trust. 
Type Therapeutic Intervention - Cellular and gene therapies
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2016
Development Status Under active development/distribution
Impact Possibly using the same concept to regulate translation of other genes 
 
Description High-Content Biology Lab Opening Symposium 
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 Other audiences
Results and Impact 120 researchers attended the Opening Symposium for the High-Content Screening facility, which sparked interest in accessing the facility from academics and industry partners.
Year(s) Of Engagement Activity 2018
 
Description MRC DPUK Stem Cell Partnership workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Postgraduate students
Results and Impact 2 day workshop for postdocs, PhD students and PIs on biology of neurodegenerative disease biology and use of stem cell derived models to study these. Researchers/students from 10-15 HEI attended
Year(s) Of Engagement Activity 2018
 
Description Panel discussion at Royal Institution 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Making monsters? Ethical gene editing

Modern stem cell and embryology research has the potential to revolutionise medicine, but some see it as 'playing God'. I was part of a panel of scientists and policy experts discussing the latest developments in genetic medicine and whether we are ready for the ethical challenges these technologies raise.
Year(s) Of Engagement Activity 2018
URL https://www.rigb.org/whats-on/events-2018/april/public-making-monsters-ethical-gene-editing
 
Description School visit 
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 Schools
Results and Impact Approx 20 school children visited the screening lab and were given hands-on introduction to research in my lab.
Year(s) Of Engagement Activity 2019
 
Description Scientific Advisory Board Expert Panel for the Dementia Discovery Fund 
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 The Scientific Advisory Board of the Dementia Discovery Fund in collaboration with Alzheimers Research UK, invited me as an expert panel member to discuss the role of Autophagy in Alzheimer's disease. The SAB (composed of leading experts in the pharmaceutical industry and charities) explored the possbility to invest in the development of autophagy modulating drugs for treatment of Alzheimer's disease. This discussion had an immediate impact on funding decisions and the policy of the Dementia Discovery Fund going forward in this area.
Year(s) Of Engagement Activity 2019
 
Description Single cell imaging 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Have for the last three years had a group of year 12 students from Brighton College visit my lab and be introduced to the work we do on Dementia. We give a talk and then they visit different parts of the lab where my lab members tell they what experiments they do and what equipment we use. We also give out leaflets from the ARUK and ASoc. We discuss careers in neuroscience and especially dementia research. I have also had individual students undertake work experience in my lab for 2-5 days where we teach them about dementia and how we do experiments. They are introduced to the equipment and where and how we get funding to conduct our research.
Year(s) Of Engagement Activity 2016,2017,2018
 
Description Talk on research as a career for girls 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact As a female in science, I gave a talk to school children at Leytonstone school on career as a researcher in neurodegeneration.
Year(s) Of Engagement Activity 2019
 
Description visit by sixth form students to our labs 
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 Schools
Results and Impact 15 sixth form students from local state schools studying science with interest in medicine, neuroscience. Saw brain in brain bank, histology, stem cell derived neuronal cultures and questioned phd student, postdoc, medics and a patient with neurodegenerative disease.
Year(s) Of Engagement Activity 2018,2019