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.
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.
Organisations
Publications
Zientek SH
(2023)
The inverse electron demand Diels-Alder cycloaddition with carbon-11 and fluorine-18: A gateway to pretargeted imaging across the blood-brain barrier.
in Journal of labelled compounds & radiopharmaceuticals
Zhao Y
(2020)
A fluorescent molecular imaging probe with selectivity for soluble tau aggregated protein.
in Chemical science
Thompson Stephen
(2019)
A novel imaging probe with selectivity for tau-oligomeric protein aggregates: In vitro evaluation and radiolabelling with fluorine-18
in JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS
Thompson S
(2020)
Handbook of Radiopharmaceuticals - Methodology and Applications
Taylor CG
(2018)
Extrinsic Amyloid-Binding Dyes for Detection of Individual Protein Aggregates in Solution.
in Analytical chemistry
Spillantini MG
(2018)
Neurodegeneration and the ordered assembly of a-synuclein.
in Cell and tissue research
Spillantini M
(2018)
Neurodegeneration and the ordered assembly of a-synuclein
Solti K
(2020)
DJ-1 can form ß-sheet structured aggregates that co-localize with pathological amyloid deposits
in Neurobiology of Disease
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 | Co-Chair of MRC 'Black in Biomedical Research' Advisory Group |
Geographic Reach | National |
Policy Influence Type | Participation in a guidance/advisory committee |
URL | https://www.ukri.org/who-we-are/mrc/how-we-are-governed/mrc-black-in-biomedical-research-advisory-gr... |
Description | Developing scientific career as a BME staff |
Geographic Reach | Local/Municipal/Regional |
Policy Influence Type | Influenced training of practitioners or researchers |
Description | UK PET Innovation Network |
Geographic Reach | National |
Policy Influence Type | Membership of a guideline committee |
URL | https://www.petnetwork.org.uk/ |
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 | 09/2018 |
End | 10/2019 |
Description | Developing chemical antibodies for sensitive and selective detection of alpha synuclein aggregates in biofluids |
Amount | $150,000 (USD) |
Funding ID | MJFF-020701 |
Organisation | Michael J Fox Foundation |
Sector | Charity/Non Profit |
Country | United States |
Start | 09/2021 |
End | 09/2023 |
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 | 09/2019 |
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 | Synthesis and characterization of novel probe for imaging aggregated protein |
Organisation | Macquarie University |
Country | Australia |
Sector | Academic/University |
PI Contribution | synthesis of compound |
Collaborator Contribution | synthesis of compound and computational analysis of binding to proteins |
Impact | increased our understanding of binding of our novel compounds to aggregated beta-sheet proteins |
Start Year | 2023 |
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 | Outreach to general public in Norwich |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | A department outreach in which we put a range of event including presentations and stall in shopping center in Norwich to highlight the research we do |
Year(s) Of Engagement Activity | 2023 |
Description | Presentation on Total Body PET technology |
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 | Very useful feedback on proposed reserch plan |
Year(s) Of Engagement Activity | 2022 |
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 | Public event for Huntington patient and carers |
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 | Patients, carers and/or patient groups |
Results and Impact | Presentations and describing to Huntington patients and carers our research in developing and PET imaging technology targeted at aggregated toxic proteisn |
Year(s) Of Engagement Activity | 2023 |
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 |