PET Markers of Oligomeric Misfolded Proteins in Neurodegenerative Disorders

Lead Research Organisation: University of Cambridge
Department Name: Wolfson Brain Imaging Centre

Abstract

A common feature of all dementias e.g. Alzheimer's, Parkinson's and Huntington's diseases are the presence of specific proteins in the brain, which due to having abnormal structures, accumulate into increasingly large assemblies and fibrils. These structures, which are present in many regions of the brain, are considered to be toxic and damage brain cells, leading to the symptoms of dementia. Using the clinical brain imaging technique of Positron Emission Tomography (PET) combined with injecting into patients chemical probes which selectively bind to these assembles we can now visualize the presence and distribution of some of these toxic proteins. However, with the present range of these chemical probes we can only image the late stages of these assemblies when most of the brain damage has occurred and so too late for effective drugs therapies. Therefore our aim is to develop next generation chemical probes that can image the earlier stages and structures of these abnormal proteins when they are considered most toxic and hence cause the most damage to brains cells. This would then create a powerful means for earlier more accurate diagnosis of dementia and a means of evaluating the new types of drugs that are been developed that target these assemblies. To discover and develop these new chemical probes, will apply chemical screening methods, medicinal chemistry, radiochemistry and biological assessments. The chemical probes with appropriate properties arising from this project we would then take forward with additional funding for human imaging studies.

Planned Impact

The impact of this project and the beneficiaries are in two main areas:

Health and Well being: The overarching aim of our programme of research is to improve health and well-being of the UK population that are affected by neurodegenerative disorders. This disorders include Alzheimer's disease, Parkinson's disease, progressive supranuclear palsy and Dementia with Lewy bodies, a range of disorders that result in increasing neurocognitive and neuropsychiatric deficits, physical disabilities and eventual death. Our novel technology would be of benefit to help understand the mechanisms and pathophysiology of these disorders and thereby develop effective treatments and therapies. Therefore, the final beneficiaries of our research outcomes will be these patients. Indirectly their families, who often carry major burden of care, will benefit and the general population through a reduction in the substantial NHS and social service budgets that arise from these disorders. Savings that would be of benefit to the nation's general economy. The projects outlined in this proposal are consistent with our overall objectives, with the target aim to introduce a powerful imaging technology that will greatly enhance and facilitate these on-going clinical research programmes of research. Due to the close relationship between the University of Cambridge and Addenbrooke's hospital, enabled by being a Comprehensive Biomedical Centre, including a Biomedical Research Unit for Dementia and major memory clinics the research outcomes of the project can also be immediately translated to inform clinical decisions on these patients. Therefore our research project will be of benefit and aid to the clinical staff responsible for the care of these patients.
Related to clinical care, diagnostic services will benefit from the development and validation of the novel PET probes we plan to develop, in particular any fluorine-18 probes, which are appropriate for clinical imaging services. These novel radiotracers will be significant additions to the growing field of molecular imaging, which can help in early diagnosis of disease, clinical characterisation and evaluation of subsequent treatment.

Wealth creation and prosperity: The development of a validated PET probe, especially for application in the early detection and characterisation of neurodegenerative diseases would be of commercial interest to the radiopharmaceutical companies e.g. GE Healthcare, PETnet, and Alliance Medical who have established manufacturing sites in the UK to underpin the increasing use of PET diagnostic service in the NHS. We would exploit the commercial potential of these PET probes to the financial benefit of both the university and the radiopharmaceuticals company, through partnership.
The UK pharmaceutical industry would also benefit from the outcome of these projects. Applying the increased understanding of PET imaging to research into these pathologies to develop more effective drugs. This need is now more pressing with the emergence of novel therapeutics (e.g. immunisation therapies) that targets early stages of the disease process for which there is an urgent requirement for in vivo biomarkers for assessing their efficacy. Therefore the availability of these PET probes would be a powerful tool for clinical trials on novel drugs. The relocation of Medimmune and AstraZeneca to the Cambridge Biomedical Campus (CBC) site with their human antibody therapy programmes, means that they could obtain immediate benefit of these new technology.

Publications

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Bevan-Jones RW (2018) [18F]AV-1451 binding is increased in frontotemporal dementia due to C9orf72 expansion. in Annals of clinical and translational neurology

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Spillantini MG (2018) Neurodegeneration and the ordered assembly of a-synuclein. in Cell and tissue research

 
Description We have synthesised a novel range of compounds that have good binding affinity to synuclein fibrils . These compounds have shown that good binding affinity can be achieved by designing different linkers lengths between two of more chemotypes.
We have also developed a compound that has been shown to have good selectivity to tau oligomeric species . This would be the first time this has been achieved.
we have shown for the first time the binding of tau PET compound to pathology in rat model.
We are developing a novel approaching for getting radiopharmaceutical to cross the blood brain barrier
Exploitation Route Are aim is to assess more of novel compounds for binding to oligmeric preotine . Ina ddition to radiolabell our lead oligomeric probes and perfrom in vivo studies in an animal model.
we also work with clinical colleague to assess if can be used to detect oligmers in human brain tisssue
Sectors Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Dementia Platform UK Executive Team
Geographic Reach National 
Policy Influence Type Participation in a advisory committee
Impact Support the mission of Dementias Platform UK (DPUK) to accelerate the development of treatments for dementia - in particular in the application of imaging for experimental medicine . Therefore toward increasing survival and quality of life for patients with dementia
URL https://www.dementiasplatform.uk/
 
Description Developing scientific career as a BME staff
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
 
Description A New Method to Develop PET Ligands for Protein Aggregates in Neurodegenerative Disorders Using Soluble Brain-Derived Aggregates
Amount £783,024 (GBP)
Funding ID EP/T01427X/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 03/2020 
End 02/2023
 
Description A preclinical PET-CT scanner for advancing dementia research
Amount £150,000 (GBP)
Funding ID ARUK-EG2018B-001 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2018 
End 10/2019
 
Description Molecular Imaging Chemistry Laboratory (MICL) - A Innovation and Translation Hub for PET Probes
Amount £75,000 (GBP)
Funding ID n/A 
Organisation Cambridge Clinical School 
Sector Academic/University
Country United Kingdom
Start 10/2019 
End 09/2020
 
Title RVG virus /PET probe complex 
Description We have develop an approach that involves an immunogenically silent peptide fragment originated from the rabies virus glycoprotein (RVG) to transport the radiopharmaceutical into central nervous system . Shown this technology can be applied to achieve good brain uptake for a non-labelled PET compound which does not normally cross the BBB. Critically, without modifying the compound to incorporate anionic properties, previously considered essential for this technology to work, potentially simplifying the method and making it more widely applicable 
Type Of Material Technology assay or reagent 
Year Produced 2019 
Provided To Others? No  
Impact This could have major impact for developing new radiopharmaceuticals e.g.access to chemical entities that are presently considered impermeable to the CNS.Further work is now being done with an aim for patent of technology 
 
Title novel PET radiotracers for imaging alpha-synuclien fibrils 
Description We have designed a novel set of compounds with high affinity and good selectivity for alpha -synuclein fibril. The have now been radiolabelled with PET radioisotope 
Type Of Material Technology assay or reagent 
Year Produced 2018 
Provided To Others? No  
Impact This novel radiotracer has potentail to be used for taking foward for developmnet for future use in clincal PET imaging . They have are also estabslihed a new approach for designing high affinity compounds for aggregated misfolded proteins 
 
Title novel in vitro marker of oligomeric pathology 
Description A new fluorescent compound which has shown to bind with good selectivity to oligomeric aggregated protein 
Type Of Material Technology assay or reagent 
Year Produced 2018 
Provided To Others? No  
Impact This basis and lead compound for developing a novel PET radiotracer for imagining oligomer in vivo 
 
Description Characterising binding of tau PET radiotracers in transgenic rat models of dementia 
Organisation AXON Neuroscience SE
Country Slovakia 
Sector Private 
PI Contribution Radiosynthesis of radiotracers, in vitro assessment , in vivo imaging and data analysis
Collaborator Contribution AXON Neuroscience will supply transgenic rat models - brain tissue and live animals
Impact obtained a MRC Proximity to Industry grant ,
Start Year 2017
 
Description Collaboration in PET imaging with Fudan University 
Organisation Fudan University
Country China 
Sector Academic/University 
PI Contribution In discussion
Collaborator Contribution In discussions
Impact Not as yet
Start Year 2019
 
Description Collaboration with AR-UK Drug Discovery Insititute on developing PET marker for oligomers 
Organisation Alzheimer's Research UK
Department Alzheimers Research UK, Cambridge
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution As outlined in the EPSRC project proposal
Collaborator Contribution Bringing there expertise in dug discovery and development to the project and when appropriate undertake some biophysical characterisation of lead compound
Impact N/A
Start Year 2017
 
Description purpose of binding profiles of a novel compound to beta-sheet proteins in particular beta-amyloid 
Organisation Heinrich Heine University Düsseldorf
Country Germany 
Sector Academic/University 
PI Contribution Synthesis of novel compound which binds to oligomeric aggregated pathology
Collaborator Contribution Characterise the binding profile of this novel compound to beta sheet proteins using their new method of QIAD
Impact We have now determined binding profile of this novel compund and now writing a manuscript for publication from the results.
Start Year 2017
 
Description ARUK Cycle2Corfu event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Supporters
Results and Impact Meet and thank ARUK supporter that raised funds for the charity . Explain the what there funds will be used for
Year(s) Of Engagement Activity 2019
 
Description Debate on Univeristy Racial Equalty Charter 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact Talk and debate on the aspect of the racial Equality charter and its porgression and impact within the univeristy of Cambridge
Year(s) Of Engagement Activity 2020
 
Description Presentation to Schmidt Felowship 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact talk and dicussion with Schmidt Science Fellows . The aim to create a new generation of scientific leaders with vision is to give the world's best aspiring scientific minds a broader perspective, the ability to engage in an interdisciplinary way, and the opportunity to make a lasting impact on society
Year(s) Of Engagement Activity 2020
 
Description Webinar to Society of Neuroscientists of Africa 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Talk and dicussion on aspect of being a BAME scientist to the Society of Neuroscientists of Africa (SONA) is the umbrella organisation for the regional and national neuroscience societies and groups in Africa,
Year(s) Of Engagement Activity 2020
URL http://www.youtube.com/channel/UCvSiEt9aShrhpC6u86yBsgw