MICA: Dementias Platform UK 2 - Integrated Dementia Experimental Medicine

Lead Research Organisation: University of Oxford
Department Name: Psychiatry

Abstract

DPUK is a public-private partnership to accelerate the development of new treatments for dementia. Since inception (2014) DPUK has increased the UK capacity for dementia research through infrastructure development and strategic data collection, leveraging a further £74.4m for dementia research.

The second phase of DPUK (DPUK2) focuses on developing UK capacity for dementia experimental medicine. A major challenge in developing new treatments is understanding the mechanisms through which a drug might operate. This involves precision studies where individuals of known vulnerability to specific causes of dementia are recruited to studies of cause-specific mechanistic pathways. These studies are very difficult to do as they require detailed assessment of volunteers before the study begins and standardising all the procedures in centres across the UK. These studies are also high risk in that there is no guarantee of success.

DPUK2 addresses these issues head-on at two levels. First it uses the UK's rich legacy in population cohort studies to identify suitable volunteers by using and enhancing existing cohort data. Second it creates a pre-competitive environment that brings together industry, academic and third-sector entities into partnership. This not only shares the costs and risks of experimental medicine (EM) studies, it also shares the benefits amongst a wider spread of stakeholders, each able to exploit the findings. DPUK2 does this through 3 inter-dependent work-streams.

1. The Data Portal (DP): The DP is a world leading end-to-end dementia focused data management solution. It enables large and complex datasets to be accessed remotely from around the globe without compromising data security. The DP is being developed in partnership with Health Data Research UK (HDR UK) so that we can maximise the data available to dementia research. The DP is used to manage all the data and information systems necessary for conducting precision studies. It brings large and complex datasets together in order to test new ideas; it manages personal information securely to enable recruitment to precision studies; it manages many types of data so that genetics, brain imaging, cognitive performance; and questionnaire data can all be analysed together.

2. The Trials Delivery Framework (TDF): The TDF is the vehicle that enables the DPUK2 experimental medicine programme to be efficient. The TDF organises our Clinical Studies Register (CSR) through which cohort members can volunteer for experimental medicine studies. The CSR allows us to contact members to enrich their data in terms of background information, cognitive testing, and where necessary genetics. As part of the CSR, and in partnership with the Alzheimer's Society, we have a PPI programme to understand what best practice is in terms if recruitment to experimental medicine studies. The TDF also enables us to identify centres of excellence across the UK for conducting experimental studies rigorously. This not only assures data quality, but also means that volunteers do not have to travel too far to participate.

3. The EM Incubator: The incubator is where our partners meet to plan and execute the experimental medicine programme. It has three themes; the first is Vascular Health. This is important because so many factors that affect the heart also affect the brain. If any area is likely to have drugs that already exist and could be re-purposed for dementia, this is it.The second theme is Synaptic Health. Here we investigate factors that affect the loss of neuron synapses. This is important because unlike neurons, synapses (the connections between neurons), can be generated, which is critical to learning and maintaining memory. The third area is Neuroimmunology. This is important as inflammation is a systemic problem that is known to affect the brain and might have systemic solutions, and so represents a promising area for new treatments.

Technical Summary

The objectives of the Dementias Platform UK renewal (DPUK2) are to:
1. Increase the precision of experimental medicine (EM) through precision phenotyping according to genetic risk
2. Increase the capacity of EM through streamlined systems and integrated informatics
3. Increase the opportunity for EM through agile and adaptive global partnerships

These will be achieved through three inter-dependent workstreams comprising:

1. Workstream A The Data Portal: The Data Portal will be enhanced to provide secure and auditable data management with an on-premise cloud, and hybrid solutions for :
- Observational and EM multi-modal data discovery
- In silico experiments including multi-modal and machine learning analysis
- Enriched phenotyping for the Clinical Studies Register
- Knowledge development and preservation

2. Workstream B The Trials Delivery Framework (TDF): The TDF will provide a recruitment and study delivery mechanisms for dementia experimental medicine:
- Pre-clinical recruitment via the Clinical Studies Register
- Early disease recruitment via existing NIHR and NHS investments (Join Dementia Research, BRCs, memory clinics)
- Trial delivery centre network drawn from existing structures including the DPUK imaging network, EPAD and NIHR TRC-D and BRCs.

3. Workstream C The EM Incubator: The EM incubator nurtures academic-industry partnerships for precision mechanistic EM studies, demonstrating the value of this approach through a series of pump-prime funded experiments on:
WP 5- Vascular Health
WP 6- Synaptic Health
WP 7- Neuroimmunology

DPUK2 aims to develop its EM portfolio according to scientific interest and further funding.

Planned Impact

The main aim of DPUK2 is to use precision experimental medicine (EM) to reduce the mechanistic uncertainty surrounding the discovery of new treatments for dementia. To achieve this we will bring together the essential stages of EM workstreams - vascular, synaptic health and neuroinflammation. With a clear focus on identifying appropriate biomarkers for treatment stratification, there will be many beneficiaries, including dementia patients, their families and the wider population upon which much of the economic burden falls. We outline the immediate areas of academic and non-academic impact for DPUK2:

Academic sector
The Data Portal is a key development in the open science agenda, offering increased opportunity and economies of scale and efficiency. Scientists around the world can access an exceptional breadth of data for rapid data discovery and hypothesis testing. Additionally the implementation of a single common data model across datasets offers researchers unprecedented resource savings in data preparation, and enhanced access for cross-cohort data analysis.

The trials delivery framework addresses the fragmented nature of dementia-related trials in the UK. By providing precision risk stratification and targeted recruitment to multi-centre studies, using a network of clinical research centres, the UK becomes more attractive for conducting rigorous, relevant, cutting-edge science. The EM Incubator offers an agile pre-competitive model for developing partnerships with industry. Benefits to academics include access to developing technologies and commercially strategic research questions.

Commercial and private sector
Precision EM, leading to the de-risking of trials, is of profound interest to molecular, cellular and systems neuroscientists working in industry to identify disease mechanisms and drug targets. DPUK2 will develop its existing profile of industry engagement and collaboration, and has appointed a lead (Declan Jones) for industry. Our strategy is based around active interaction and collaborative funding of proof of concept studies leading to larger programmes of work. Such direct engagement is necessary for meaningful translation of basic research findings. Our list of partners demonstrates the interest of industry in this model.

Public sector, policy and practice
We will continue working with other agencies in spearheading contemporary debate about neurodegenerative disease and dementia. We have appointed a lead (Carol Routledge) for the charity and philanthropy sector who has in-depth contact with UK dementia policy makers, and our partnerships include ARUK and the Alzheimer's Society (the two main UK dementia research charities). More widely we contribute to the NIHR Dementia Progress Group, setting the Dementia 2025 priorities, and to UKRI cohort data management policy discussions - the Data Portal being a key demonstration of the challenges and benefits of policy development in this area.

Public engagement
Engagement and consultation with the public, patients and carers is central to our mission. This shapes how we communicate our research findings and also how we address such issues as stigma, research relevance and the research culture within the NHS in relation to dementia. We are committed to this because neurodegeneration should be regarded as increasingly tractable to research in genetics, neuroscience, and epidemiology, and that EM is key to future progress. We will therefore promote dementia research focusing on the understanding of pathogenesis and pathophysiology, and developing new approaches to treatment.

Skills and training
We will continue to recruit and train staff and students from a wide variety of backgrounds in inter-disciplinary skills that will be widely relevant outside academia. Moreover, through our multi-disciplinary approach we will be training a new cadre of early career researchers who will be attracted to, and equipped for, careers in dementia research

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