Dementias Platform UK Stem Cell Partnership
Lead Research Organisation:
University of Edinburgh
Department Name: Centre for Clinical Brain Sciences
Abstract
A major hurdle to developing new treatments for dementias and other neurodegenerative disorders is the practical and ethical barriers to undertaking brain research in people. However, it is now possible to turn cells from skin biopsies or blood samples into stem cells, which can be grown in a dish in the lab. In turn, the stem cells can be differentiated into any cell type, including brain cells. This allows study of the cell processes affected in dementia and other neurodegenerative diseases in human cells, and has potential in identifying and testing new therapies.
This proposal brings together six UK stem cell Centres recently supported by the MRC Dementias Platform UK (Cambridge, Cardiff, Edinburgh, Manchester, Oxford and University College London). This Dementia Stem Cell Network will provide a step change in UK dementia stem cell research and feed into drug discovery initiatives to find novel dementia treatments.
Our proposed Partnership will significantly increase the capacity, competitiveness and effective use of resources of UK dementia stem cell research by helping us work together as a coordinated stem cell network.
The technology involved in producing brain cells from stem cells is relatively new and evolving at a rapid pace. The Partnership will create a unique, deeply studied collection of cells donated by volunteers with dementia, plus from healthy individuals to compare them against. These cells can be grown in the lab indefinitely, and will form a global and powerful stem cell research resource.
Critically, the Partnership will develop and validate protocols that will be harmonised across the network. In this way we can work together using state-of-the-art automated and large-scale technology to understand the biology of dementia. Our goal is to find new markers and develop robust tests for dementia that will accelerate the search for new drug treatments by pharmaceutical companies.
This proposal will deliver this programme of research and resources by appointing and training four highly skilled Network Technical Scientists. Each will be dedicated to specific scientific techniques and goals, but share expertise and findings across the Partnership and beyond. The Partnership will also produce a training programme for PhD students, who will work across at least two Centres to address important questions about dementia/neurodegenerative disease. These two programmes will future-proof the Dementia Stem Cell Network and MRC investment by equipping the UK with researchers highly skilled in stem cell technologies who will participate in multi-site interdisciplinary research. Through the Network Technical Scientists and PhD students, we will reach out to other researchers in the UK with regular meetings to involve new sites in this collaborative venture.
In summary, the Partnership will create unique shared resources and expertise to drive joined-up UK-wide dementia research with the goal of identifying new disease modifying treatments.
This proposal brings together six UK stem cell Centres recently supported by the MRC Dementias Platform UK (Cambridge, Cardiff, Edinburgh, Manchester, Oxford and University College London). This Dementia Stem Cell Network will provide a step change in UK dementia stem cell research and feed into drug discovery initiatives to find novel dementia treatments.
Our proposed Partnership will significantly increase the capacity, competitiveness and effective use of resources of UK dementia stem cell research by helping us work together as a coordinated stem cell network.
The technology involved in producing brain cells from stem cells is relatively new and evolving at a rapid pace. The Partnership will create a unique, deeply studied collection of cells donated by volunteers with dementia, plus from healthy individuals to compare them against. These cells can be grown in the lab indefinitely, and will form a global and powerful stem cell research resource.
Critically, the Partnership will develop and validate protocols that will be harmonised across the network. In this way we can work together using state-of-the-art automated and large-scale technology to understand the biology of dementia. Our goal is to find new markers and develop robust tests for dementia that will accelerate the search for new drug treatments by pharmaceutical companies.
This proposal will deliver this programme of research and resources by appointing and training four highly skilled Network Technical Scientists. Each will be dedicated to specific scientific techniques and goals, but share expertise and findings across the Partnership and beyond. The Partnership will also produce a training programme for PhD students, who will work across at least two Centres to address important questions about dementia/neurodegenerative disease. These two programmes will future-proof the Dementia Stem Cell Network and MRC investment by equipping the UK with researchers highly skilled in stem cell technologies who will participate in multi-site interdisciplinary research. Through the Network Technical Scientists and PhD students, we will reach out to other researchers in the UK with regular meetings to involve new sites in this collaborative venture.
In summary, the Partnership will create unique shared resources and expertise to drive joined-up UK-wide dementia research with the goal of identifying new disease modifying treatments.
Technical Summary
A major hurdle to developing treatments for dementia is the lack of human models to study disease mechanisms. However, induced pluripotent stem cell (iPSC) technology and methods to derive neurons and glia now allow study of the pathogenic processes affected in dementia.
This proposal partners six major UK Dementia Stem Cell Centres supported by the MRC Dementias Platform UK [DPUK] (Cambridge, Cardiff, Edinburgh, Manchester, Oxford, University College London). Our Partnership capitalises on the £8M DPUK investment in technology platforms to significantly increase the capacity, competitiveness and effective resource use of UK dementia stem cell research by promoting a highly collaborative research network to feed into drug discovery initiatives.
The Partnership will create reference iPSC lines from all the major forms of dementia as well as deeply phenotyped healthy aged controls, to form a global highly phenotyped stem cell resource. Critically, we will define standard operating procedures to allow collaborative phenotyping using the DPUK technology platforms including state-of-the-art high-throughput imaging, electrophysiology, metabolomics and proteomics. Development of robust assays / phenotypes for dementia will accelerate the identification and validation of drug targets by industry and academic partners.
Four appointed Network Technical Scientists will work across the six sites. Each will be dedicated to specific techniques and goals and will disseminate expertise across the Partnership and beyond. The Partnership will also support PhD students working across Centres. The programmes will leverage existing MRC investment by equipping the UK with researchers highly skilled in interdisciplinary stem cell technology and engage new UK collaborators through regular symposia and training.
In summary, the Partnership will create unique stem cell resources and expertise to drive joined-up dementia research to identify new disease-modifying treatments.
This proposal partners six major UK Dementia Stem Cell Centres supported by the MRC Dementias Platform UK [DPUK] (Cambridge, Cardiff, Edinburgh, Manchester, Oxford, University College London). Our Partnership capitalises on the £8M DPUK investment in technology platforms to significantly increase the capacity, competitiveness and effective resource use of UK dementia stem cell research by promoting a highly collaborative research network to feed into drug discovery initiatives.
The Partnership will create reference iPSC lines from all the major forms of dementia as well as deeply phenotyped healthy aged controls, to form a global highly phenotyped stem cell resource. Critically, we will define standard operating procedures to allow collaborative phenotyping using the DPUK technology platforms including state-of-the-art high-throughput imaging, electrophysiology, metabolomics and proteomics. Development of robust assays / phenotypes for dementia will accelerate the identification and validation of drug targets by industry and academic partners.
Four appointed Network Technical Scientists will work across the six sites. Each will be dedicated to specific techniques and goals and will disseminate expertise across the Partnership and beyond. The Partnership will also support PhD students working across Centres. The programmes will leverage existing MRC investment by equipping the UK with researchers highly skilled in interdisciplinary stem cell technology and engage new UK collaborators through regular symposia and training.
In summary, the Partnership will create unique stem cell resources and expertise to drive joined-up dementia research to identify new disease-modifying treatments.
Planned Impact
Dementias represent one of the greatest medical and economic burdens to the UK. Recent advances in induced pluripotent stem cell (iPSC) technology, present for the first time a rational approach to human disease modelling to accelerate drug discovery.
Impact on commerce and policy-makers
Despite its huge potential, the uptake of iPSC technologies by industry is rightly cautious, due to concerns about standards, reproducibility and the compatibility of assays with high-throughput screening. The Partnership will address these issues directly by raising the bar on cell standards, cross-validating SOPs, and developing phenotypic readouts for high-content and high-throughput compatibility. Each of the Partners has extensive links with Pharma; continued engagement (for instance by the attendance of Pharma partners at the annual Spring School) and translation of our research to industrial platforms will be a significant outcome.
Downstream to the impact on commerce/Pharma, the ongoing activities of the Partnership are likely to influence the availability and choice of drug treatments for dementia and other neurodegenerative diseases, which will in due course be incorporated into clinical and government guidelines.
Impact on the economy
The current cost of dementia to the UK economy is estimated to be approximately £26 billion a year (www.alzheimers.org.uk): successful delivery of iPSC-enabled drug discovery will therefore have major economic benefit. Besides future forecasts for impact on drug discovery, iPSC technology is also of growing importance to the academic and industrial research base of the UK, with several new industries emerging to service the reagents and technology needs of the research. The four Network Technical Scientists are newly created positions whose post-holders will become experts with unique and highly desirable/marketable skill-sets. Overall, the activity of the Partnership, particularly with its emphasis on technology, is likely to positively influence this new industry and create new jobs to increase UK competitiveness. The project also has potential to generate novel IP of commercial value.
Impact on dementia patients, carers and the public
The fact that iPSCs are patient-derived places patients at the heart of the project. iPSC technology utilises patient genetics in a way that has hitherto not been possible; moreover, our strategy to develop models using genetically and clinically stratified patient cohorts - a major UK / NHS strength - recognises the diversity in dementia aetiology and manifestation, and will provide tools that discriminate phenotypes and potentially tailor drug development to different patient groups. The Partnership deliverable of the 'Dementia CellPlate' is a direct step towards this objective.
Patients and carers will be engaged in the project directly through interaction with the clinicians and researchers at the clinic or at patient focus/support groups. More widely, we will inform and engage the public through print and online media (press releases, websites, blogs, social media). We will place emphasis on explaining the technology in an accessible way such that it can provide real hope for the future.
Impact on the public and third sectors
We have formed partnerships with major charities related to dementia and neurodegenerative disease: Alzheimer's Society (AS), Alzheimer's Research UK (ARUK) and the Motor Neurone Disease Association (MNDA). AS and MNDA have agreed in principle to support PhDs in association with this Partnership; ARUK is co-funding a proof of concept collaborative project (see Addendum to Case for Support). In addition, early-career researchers in the Partners' laboratories are supported by these charities and others, and will benefit from the Partnership by attendance at training days and symposia. We will work closely with these charities to align and communicate our findings.
Impact on commerce and policy-makers
Despite its huge potential, the uptake of iPSC technologies by industry is rightly cautious, due to concerns about standards, reproducibility and the compatibility of assays with high-throughput screening. The Partnership will address these issues directly by raising the bar on cell standards, cross-validating SOPs, and developing phenotypic readouts for high-content and high-throughput compatibility. Each of the Partners has extensive links with Pharma; continued engagement (for instance by the attendance of Pharma partners at the annual Spring School) and translation of our research to industrial platforms will be a significant outcome.
Downstream to the impact on commerce/Pharma, the ongoing activities of the Partnership are likely to influence the availability and choice of drug treatments for dementia and other neurodegenerative diseases, which will in due course be incorporated into clinical and government guidelines.
Impact on the economy
The current cost of dementia to the UK economy is estimated to be approximately £26 billion a year (www.alzheimers.org.uk): successful delivery of iPSC-enabled drug discovery will therefore have major economic benefit. Besides future forecasts for impact on drug discovery, iPSC technology is also of growing importance to the academic and industrial research base of the UK, with several new industries emerging to service the reagents and technology needs of the research. The four Network Technical Scientists are newly created positions whose post-holders will become experts with unique and highly desirable/marketable skill-sets. Overall, the activity of the Partnership, particularly with its emphasis on technology, is likely to positively influence this new industry and create new jobs to increase UK competitiveness. The project also has potential to generate novel IP of commercial value.
Impact on dementia patients, carers and the public
The fact that iPSCs are patient-derived places patients at the heart of the project. iPSC technology utilises patient genetics in a way that has hitherto not been possible; moreover, our strategy to develop models using genetically and clinically stratified patient cohorts - a major UK / NHS strength - recognises the diversity in dementia aetiology and manifestation, and will provide tools that discriminate phenotypes and potentially tailor drug development to different patient groups. The Partnership deliverable of the 'Dementia CellPlate' is a direct step towards this objective.
Patients and carers will be engaged in the project directly through interaction with the clinicians and researchers at the clinic or at patient focus/support groups. More widely, we will inform and engage the public through print and online media (press releases, websites, blogs, social media). We will place emphasis on explaining the technology in an accessible way such that it can provide real hope for the future.
Impact on the public and third sectors
We have formed partnerships with major charities related to dementia and neurodegenerative disease: Alzheimer's Society (AS), Alzheimer's Research UK (ARUK) and the Motor Neurone Disease Association (MNDA). AS and MNDA have agreed in principle to support PhDs in association with this Partnership; ARUK is co-funding a proof of concept collaborative project (see Addendum to Case for Support). In addition, early-career researchers in the Partners' laboratories are supported by these charities and others, and will benefit from the Partnership by attendance at training days and symposia. We will work closely with these charities to align and communicate our findings.
Publications
Braems E
(2022)
HNRNPK alleviates RNA toxicity by counteracting DNA damage in C9orf72 ALS.
in Acta neuropathologica
Bogetofte H
(2023)
Post-translational proteomics platform identifies neurite outgrowth impairments in Parkinson's disease GBA-N370S dopamine neurons.
in Cell reports
Beckers J
(2023)
A toxic gain-of-function mechanism in C9orf72 ALS impairs the autophagy-lysosome pathway in neurons
in Acta Neuropathologica Communications
Banerjee P
(2022)
NLRP3 inflammasome as a key molecular target underlying cognitive resilience in amyotrophic lateral sclerosis.
in The Journal of pathology
Banerjee P
(2023)
Cell-autonomous immune dysfunction driven by disrupted autophagy in C9orf72-ALS iPSC-derived microglia contributes to neurodegeneration.
in Science advances
Description | (SAND) - Secretion, Autophagy and their role in Neurodegeneration |
Amount | € 4,137,646 (EUR) |
Funding ID | 860035 |
Organisation | European Commission |
Sector | Public |
Country | European Union (EU) |
Start | 11/2019 |
End | 10/2023 |
Description | Accelerated drug discovery for MND using human stem cell based phenotypic screening |
Amount | £24,666 (GBP) |
Organisation | MND Scotland |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2020 |
End | 08/2021 |
Description | Human Stem Cell "discovery In A Dish" Approach To Identify, Validate And Prioritise Existing Medicines |
Amount | £250,000 (GBP) |
Organisation | My Name'5 Doddie Foundation |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2018 |
End | 02/2021 |
Description | INTRAR-MND initiative |
Amount | £190,000 (GBP) |
Funding ID | RFA/18/01 |
Organisation | Chief Scientist Office |
Sector | Public |
Country | United Kingdom |
Start | 11/2018 |
End | 11/2022 |
Description | MND Collaborative Partnership (United2EndMND) |
Amount | £4,249,999 (GBP) |
Organisation | LifeArc |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2023 |
End | 06/2025 |
Description | MND-SMART - Motor Neurone Disease Systematic Multi-Arm, Multi-Stage Adaptive Randomised Trial |
Amount | £1,500,000 (GBP) |
Organisation | MND Scotland |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 11/2018 |
End | 10/2023 |
Description | MS Society Edinburgh Centre For MS Research 2021-2025 |
Amount | £1,847,140 (GBP) |
Funding ID | 133 |
Organisation | Multiple Sclerosis Society |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2021 |
End | 12/2025 |
Description | Cedars Sinai Collaboration |
Organisation | Cedars-Sinai Medical Center |
Country | United States |
Sector | Hospitals |
PI Contribution | Team led by Prof Clive Svendsen at Cedars Sinai are reprogramming all Lothian Birth Cohort samples. |
Collaborator Contribution | Generating iPSCs |
Impact | None yet |
Start Year | 2017 |
Description | ALS Gordon Research Conference 2017 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Research Talk |
Year(s) Of Engagement Activity | 2017 |
URL | https://www.grc.org/amyotrophic-lateral-sclerosis-als-and-related-motor-neuron-diseases-conference/2... |
Description | Age UK Wireless interview with Sir Martyn Lewis |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Radio Interview |
Year(s) Of Engagement Activity | 2017 |
Description | Dementia health inequalities report |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | Dementia health inequalities report |
Year(s) Of Engagement Activity | 2022 |
URL | https://ukdri.ac.uk/uploads/UK-DRI_Dementia_Health_Inequalities_Report_2022.pdf |
Description | MND-Scotland Peer Support Group visit |
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 | Supporters |
Results and Impact | Visit by MND Scotland Patient Support Group members. |
Year(s) Of Engagement Activity | 2022 |
Description | Media Interview |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | BBC Alba Interview |
Year(s) Of Engagement Activity | 2018 |
Description | Progressive Supranuclear Palsy - research working group meeting |
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 | Formal working group research update meeting with primary donor. |
Year(s) Of Engagement Activity | 2021,2022,2023 |
Description | Public - NHS talk "Advanced Therapies for Neurodegenerative Diseases" |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | NHS Lothian Annual Research Day showcasing research in NHS. Clinical Research : driving efficient, innovative and effective healthcare. |
Year(s) Of Engagement Activity | 2017 |
Description | Public Lecture |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Regional Multiple Sclerosis Patient Group |
Year(s) Of Engagement Activity | 2017 |
Description | Public Talks |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | Public talk in Stornaway to mixed audience |
Year(s) Of Engagement Activity | 2018 |
Description | Race Against Dementia Annual Scientific Review |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Supporters |
Results and Impact | Scientific review meeting with sponsors and PhD students. |
Year(s) Of Engagement Activity | 2021 |
Description | Race Against Dementia Donor Event |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Supporters |
Results and Impact | Presentation/talk at major donor event. |
Year(s) Of Engagement Activity | 2021 |
Description | Race Against Dementia Research PhD programme - Summer School 2022 |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Annual summer school for Race Against Dementia Summer School PhD students. |
Year(s) Of Engagement Activity | 2022 |
Description | Talk at International Meeting - India |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Postgraduate students |
Results and Impact | Talk on human stem cell based modelling of neurodegenerative diseases at NCBS / inStem in Bangalore. This is a major biomedical research cluster in India. |
Year(s) Of Engagement Activity | 2017 |
Description | Talk to Undergraduates - Newcastle University |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Undergraduate students |
Results and Impact | Newcastle Undergraduate Neuroscience Society |
Year(s) Of Engagement Activity | 2018 |
Description | Talks at Swiss Drug Development Meeting |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | National Drug Development Conference |
Year(s) Of Engagement Activity | 2017 |
Description | UK DRI Macroglia symposium 2022 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other audiences |
Results and Impact | Annual DRI macroglial symposium event 2022 |
Year(s) Of Engagement Activity | 2022 |