Dementias Platform UK Stem Cell Partnership

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.

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.

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.