Experimental Medicine

To create the context for this new generation of studies a broad definition of experimental medicine is adopted. In addition to ‘bona fide’ experiments in which there is a manipulandum, studies contributing to the development of experimental programmes in man are included, such as:

  • Technology and methods development
  • Improving the knowledge base through preliminary data analysis, in-silico experiments, and the targeted collection of observational data
  • Enabling the convergence of technologies and expertise

EM Research Themes

The focus of the DPUK EM program is to accelerate the development of interventions through identifying neuropathologic and neuroprotective pathways and mechanisms. DPUK EM strategy is to facilitate synergy across disciplines and technologies establishing expert working groups for specific research themes, each with an academic lead and industry partner support. Currently these groups are UK based but international interest is welcome.

DPUK EM working groups are encouraged to develop systematic and coordinated programmes of work that will be competitive for strategic funding. Given the complexity of these pathways and mechanisms DPUK has prioritised three EM themes:

 

 

Experimental Medicine Theme 1: Synaptic Health

Led by Dr. Declan Jones and Dr. James Rowe

Synaptic loss and regeneration is a highly dynamic process that persists throughout adulthood, and unlike neuronal loss, which is irreversible, synaptic regeneration can be promoted. A greater understanding of synapse function, loss and repair, would enable therapies to be developed to retard synapse degeneration and enhance synapse repair.

Progress highlights:

  1. A shared understanding of the state-of-the-art in SH, and the readiness for translating the current evidence from animal models and healthy humans into clinical cohorts
  2. Consensus on the contribution from genetic models and cellular models, while keeping the future DPUK-SH focus on human studies and clinical pull-through.
  3. Knowledge sharing in terms of technologies and analyses available to manipulate synaptic function, assess cognitive impact, and potential for early diagnosis
  4. Establishing common ground between partners on the mutual priorities for robust deliverables in a cost-effective and timely research program:
  5. SH will focus on human observational and interventional studies, with disease modification (including immunotherapies and BACE inhibition) as a priority over pharmacological symptom alleviation.
  6. MEG and EEG, with advanced modelling of the human neurophysiology, are the major methods in the forthcoming applications, but not to the exclusion of other contributory methods.

Following the DPUK launch, two SH related EOIs were submitted to the first call for EM project proposals: one proposing a strategic approach to clinical measurement of SH and one using APOε4 and BDNF status to assess cognitive risk.

Experimental Medicine Theme 2: Innate and Adaptive Immunity

Led by Prof. Paul Morgan

Evidence implicating the immune system and inflammation in dementia is growing. A convergence of mechanisms has been observed in Alzheimer’s disease (AD), Parkinson’s disease (PD) and Amyotrophic lateral sclerosis (ALS), in which neuronal damage promotes neurotoxic microglial hyperactivity. Targeted ant-inflammatory therapies to regulate glial related inflammatory response may have broad application across neurodegeneration.

Four inflammation related EOIs have been submitted to the DPUK calls for EM project proposals: one using PET and MR imaging to ascertain neuroinflammatory status and link with cognitive function; one using low dose, intravenous lipopolysaccharide to stimulate a short term inflammatory response to investigate microglial activation; one using PET to investigate astrocyte activity and cognitive performance; one completing a Mandelian Randomisation study – Inflammation, cognitive function and dementia.

Strategy group:

Preliminary scoping has identified an existing expert community that has formed around a recently funded Wellcome Strategic Award. Prof Paul Morgan, who is a co-applicant on the award, will liaise with the consortium to establish a DPUK expert strategy group, including consortium members, who will identify preferred hypotheses then develop and submit proposals to the platform.  Early discussions of the group will focus on:

Translating evidence from animal models into human models, Translating evidence from genetic models to cellular models and Challenging underpinning assumptions:

  1. Inflammation is an early event in the genesis of dementias
  2. Systemic inflammation is a trigger to central damage
  • Inflammation and Immune biomarkers may predict disease
  • Identifying core themes within the Immunology and Inflammation framework:
    1. Markers of inflammation and immune cell activation
    2. Signalling pathways and immune cell activation
    • Imaging inflammation in dementias

    To initiate discussion within a newly forming group a presentation was given at the DPUK Scientific Symposium, a copy of the presentation is available here.

Experimental Medicine Theme 3: Vascular Disease Mechanisms (VDMs)

Led by Joanna Wardlaw (University of Edinburgh)
Facilitator: Paul Wren (GSK & DPUK Exec)

Introduction:

Epidemiological, genetic, neuroimaging and clinico-pathological data indicate vascular mechanisms as fundamental risk factors for Dementia. These are intrinsic in Vascular Dementia with an extensive overlap between neurodegenerative and vascular factors defining significant mixed dementia populations. Considering that mixed dementia is the most common cause of dementia in the elderly, it has become increasingly important to harmonize basic science, translational, and clinical approaches that includes the integration of a deeper understanding of the contribution of peripheral and central vascular disease mechanisms in diverse dementia populations.

The high level aims of this theme:

‘General’

·         Raise awareness of vascular disease

·         Enhance protocols to ensure vascular relevance

·         Integrate with other UK and international initiatives

‘Specific’

·         Early markers of vascular dysfunction

·         Vascular dysfunction risk factors

·         Identify interventions

The Strategy group (see Annex):

An expert group has been established including senior clinical and pre-clinical researchers, expertise in large multicenter clinical trials, observational mechanistic studies, imaging including analysis, neuropathology, experimental models, stem cells, regulatory processes, and evidence synthesis, that will use early studies to identify barriers and facilitators to developing a coordinated programme of work on how VDMs contribute to risk of and decline in Dementia. The vision is that this will help determine how interventional studies may be conducted inclusive of the employment of diverse endpoints to identify cost-effective, predictive and sensitive early biomarkers of vascular disease mechanisms in humans that may be back translated into animals/stems cells in the future.

The group are currently focussing on developing three strategies:

i)          initiating: through approved DPUK seed funding, explore the potential linkage of lipid profiles (with the NPC) from banked blood plasma samples with established neuroimaging correlates of cerebro-vascular disease with cognitive decline in the LBC1936 cohort.

ii)         building: to evolve a range of EM proposals that introduces vascular concepts into  tissue banking, compares cardiac to brain vascular phenotypes and explores vascular imaging correlates of various vascular phenotypes including eg cerebral amyloid angiopathy.

iii)        enabling: to gather vascular information from the DPUK cohorts; standard vascular disease risk factors, cardiac, systemic and cerebro-vascular disease burdens to understand the variance and gaps in data to help inform future EM proposals.

There have been five meetings of the VDM group, who are also supporting other scientists to help define and develop a range of project ideas, and avenues for future funding opportunities. A presentation of the outputs given at the DPUK Scientific Symposium is available on the website www.dementiasplatform.uk.

First award for Experimental Medicine project: August 15

Principle Investigator: Professor Ian Deary at the University of Edinburgh

Title: How do peripheral and central vascular markers relate to cognitive decline?

Award: £91,000

Summary: to look into the associations between lipidomics and cognitive function and brain imaging in the Lothian Birth Cohort 1936, which is a population study following people in Scotland since they were 11 years old. With the rich and longitudinal cognitive and brain data in the cohort we can test hypotheses about lipidomics variables as both outcomes and potential causes of cognitive differences, and we’ll map their associations with brain health, especially white matter.

Results Expected: initial results from this research are expected Autumn 16.

Read about the First award in more detail

Second award for Experimental Medicine project: October 15

Principle Investigator: Professor Richard Wade-Martins from Oxford University

Title: Integration of clinical and cellular phenotypes in the MRC NIHR Deep and Frequent Phenotype Cohort.

Award: £100,000

Summary: this project will test the hypothesis that the cellular phenotype induced pluripotent stem cell (iPSC-derived) neurons from patients, will recapitulate the clinical phenotyping using an extensively “deep phenotyped” AD cohort. The use of iPSC-derived neurons allows us to study the cells affected in AD which have previously been inaccessible, hidden deep in the brain. We will compare for the first time the relationship between the level of Abeta pathology revealed by imaging a patient, with the response of cortical neurons and synapses derived from same patient to A-beta protein in a dish. We are excited about the ability to directly relate a clinical phenotype of a patient to a cellular phenotype in the lab.

Results Expected: initial results from this research are expected Autumn 16.

Read about the Second award in more detail

Third award for Experimental Medicine project: November 15

Principle Investigator: Professor Paul Matthews from Imperial College London

Title: Multi-modal imaging correlates of Astroglial activation, β-amyloid deposition and neuronal activity as markers of cognitive impairment in AD.

Award: £21,000 from DPUK which is supplemented by significant collaborative working (Imperial, Kings College London & the Imanova Clinical Imaging Centre) with in-kind contributions covering PET and MRI scan costs provided by DPUK industry partner – GSK.

Summary: This pilot study will characterise the brain uptake of the novel astroglial activation imaging marker, [11C]BU99008, in AD subjects compared to non-AD control subjects. Relationships between [11C]BU99008 brain uptake, Aβ deposition and brain glucose metabolism will also explore how multi-modal imaging indices may inform.

Results Expected: initial results from this research are expected Autumn 16.

Read more about the Third award in more detail

Experimental Medicine Process for accessing support

Background

The vision of DPUK is to provide an integrated research environment for dementias research to accelerate the development of new interventions, focussing on utilising cohorts to support experimental medicine (EM) programmes.

The DPUK Research Strategy provides a framework for the EM themes by identifying priorities and outlining mechanisms for research across the Platform.

Introduction

The DPUK definition of EM is broad to encourage innovation and collaboration, but is human focussed.   A guidance note has been written to provide information for researchers wishing to submit proposals to DPUK for support with EM projects, this is available to download.

The DPUK EM strategy is to facilitate synergy across EM theme working groups and across technology networks in order to develop systematic and coordinated programmes of work.

DPUK EM Funding Model

The model has four components:

  1. To use the limited resources available to the platform to pump-prime the use of platform resources for dementia experimental medicine
  2. To increase the industry contribution by increasing the number of industry partners
  3. To work with scientists in using platform infrastructure to prepare competitive and strategic research proposals to major funders.
  4. To work with funders to develop funding streams that are more suited to the needs of dementia related experimental medicine. DPUK is particularly interested in working with funders to identify research priorities and to identify early phase studies that will de-risk the conduct of larger, more expensive research programmes and trials.

How to request DPUK funding support

Expressions of interest are reviewed regularly by the Executive Team (at least quarterly). Therefore we welcome proposals to be submitted at any time. Occassionally DPUK will put out particular calls for expressions of interest. These will be announced here and through Twitter.

Please refer to the Guidance Sheet and Assessment Criteria to assist you in completion of the Expression of Interest form. We are happy to answer any questions, please submit your query by using the form on the Contact Us page. Downloads below:

GUIDANCE

EXPRESSION OF INTEREST FORM

ASSESMENT CRITERIA

PROCESS FLOWCHART

STAGE 2 PROPOSAL

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