Stem Cells, Prion Proteins and Alzheimer's Diseases: A Prion Chemical Biology Network (PCBNet)
Lead Research Organisation:
University of Sheffield
Department Name: Chemistry
Abstract
Cellular prion protein, PrPC, is a membrane-anchored glycoprotein encoded by the human Prnp gene located on chromosome 20. PrPC is expressed ubiquitously, but at significantly higher levels in neuronal cells. It is highly conserved across vertebrates and has been shown to exhibit a diverse range of biological activities associated with many developmental processes and a number of normal and abnormal conditions including memory, neuroprotection, Transmissible spongiform encephalopathy (TSE), Alzheimer's diseases (AD) and cancer etc.
Unfortunately, the exact mechanisms for each of the above normal or abnormal conditions are yet to be confirmed despite significant investment from research councils and government. Contributing to this lack of understanding is a dearth of breakthroughs in prion chemical biology research. Prion research over the past decade has been coordinated by joint funders (EPSRC, BBSRC, MRC, and Department of Health, DEFRA and other major research councils and charity) with a very broad remit mainly focusing on TSE research. As a result, many other prion related research areas are less well coordinated and severely underfunded. Here we propose to establish a prion chemical biology network to promote multidisciplinary collaborative research underpinning the role of prion protein in stem cell and development and ageing-related neurodegenerative diseases such as AD, so as to provide a platform for the rapid translation of underpinning research into prion related drug discovery and intervention towards regenerative medicine and combating neurodegenerative disease. Building up strong consortia to attract more future research funding will be the key outcome of this proposed network.
The network will seek to drive prion chemical biology research into two relatively new areas of relevance to the ageing society and in personalised medicine, building on the advances in understanding, skills and facilities developed in the study of transmissible spongiform encephalopathy (TSE) over recent years: 1)The normal physiological role of prion protein in the behaviour and function of stem cells and in embryonic development; 2)The role of prion protein in ageing and neurodegenerative diseases, e.g. Alzheimer's disease (AD) and TSE.
Unfortunately, the exact mechanisms for each of the above normal or abnormal conditions are yet to be confirmed despite significant investment from research councils and government. Contributing to this lack of understanding is a dearth of breakthroughs in prion chemical biology research. Prion research over the past decade has been coordinated by joint funders (EPSRC, BBSRC, MRC, and Department of Health, DEFRA and other major research councils and charity) with a very broad remit mainly focusing on TSE research. As a result, many other prion related research areas are less well coordinated and severely underfunded. Here we propose to establish a prion chemical biology network to promote multidisciplinary collaborative research underpinning the role of prion protein in stem cell and development and ageing-related neurodegenerative diseases such as AD, so as to provide a platform for the rapid translation of underpinning research into prion related drug discovery and intervention towards regenerative medicine and combating neurodegenerative disease. Building up strong consortia to attract more future research funding will be the key outcome of this proposed network.
The network will seek to drive prion chemical biology research into two relatively new areas of relevance to the ageing society and in personalised medicine, building on the advances in understanding, skills and facilities developed in the study of transmissible spongiform encephalopathy (TSE) over recent years: 1)The normal physiological role of prion protein in the behaviour and function of stem cells and in embryonic development; 2)The role of prion protein in ageing and neurodegenerative diseases, e.g. Alzheimer's disease (AD) and TSE.
Planned Impact
The over arching objective of the proposed network is to enable the scientific community to expand its understanding of the role of prions in biology and to accelerate progress to new diagnostic and therapeutic tools for the improvement of human and animal health. The achievement of these objectives will be reliant on the engagement of several stakeholder groups. These groups include: the scientific community, commercial organisation user groups, charities, interest groups and the general public. The development of a network dedicated to the advancement of prion chemical biology would benefit each of the aforementioned stakeholder groups.
The benefit to the UK research community of the PCBNet is that it provides a forum in which chemists, biologists, engineers and medical experts can discuss, exchange and explore ideas in prion chemical biology. The realisation of the network objectives requires a collaborative multidisciplinary approach, which will be assisted by the proposed composition of the research themes. The network will act as a platform for real multidisciplinary collaboration to occur. Collaborative research in general, allows researchers to break out of their traditional restrictive boundaries, these interdisciplinary areas are key to translating research into real life situations. The network members will collaboratively generate concept notes, which will be delivered to funding bodies with the aim of shaping future funding calls. The network will also provide an opportunity for members to create consortiums to apply for large funding opportunities, engaging with both other academic research groups and commercial partners. The PCBNet will provide funding opportunities for small projects to help establish these new research partnerships.
Cellular prion proteins, PrPc, have long been associated with a family of fatal neurodegenerative diseases called Transmissible spongiform encephalopathy (TSE), more recently PrPc have been linked to Alzheimer's disease. The network will build upon existing research into TSE's to advance understanding into the role PrPc plays in the development of age related and neurodegenerative diseases. In the case of the general public the achievement of the network objectives and advancement in the understanding of age related diseases would have a direct and beneficial effect. Advancement in diagnostic techniques and therapeutic tools would result in an increased life expectancy and standard of living for Alzheimer's patients. The benefits to the interest group stakeholders, for example the Alzheimer's Society are similar in that the development of such a network has the potential to progress research into the causes, cures and prevention of these conditions. Several interest groups have accepted invitations to sit on the PCBNet management committee, this will provide these groups the opportunity to help steer the focus of the network, the acceptance of these invitations illustrates that these groups recognise and appreciate the importance of such a network.
The potential of a network dedicated to the furthering the understanding of prion proteins has been acknowledged by industry representatives from Eli-Lilly and AstraZeneca, both world leading pharmaceutical companies and from smaller commercial partners AFChemPharm and Retrogenix. The benefit of the network to commercial partners is that it will provide an opportunity to collaborate with a multidisciplinary team of experts and potentially provides early access to non-confidential research results. As the UK population ages, age related diseases will become increasingly common as such the social and economic benefits to the UK in developing treatments for these conditions could be huge.
The benefit to the UK research community of the PCBNet is that it provides a forum in which chemists, biologists, engineers and medical experts can discuss, exchange and explore ideas in prion chemical biology. The realisation of the network objectives requires a collaborative multidisciplinary approach, which will be assisted by the proposed composition of the research themes. The network will act as a platform for real multidisciplinary collaboration to occur. Collaborative research in general, allows researchers to break out of their traditional restrictive boundaries, these interdisciplinary areas are key to translating research into real life situations. The network members will collaboratively generate concept notes, which will be delivered to funding bodies with the aim of shaping future funding calls. The network will also provide an opportunity for members to create consortiums to apply for large funding opportunities, engaging with both other academic research groups and commercial partners. The PCBNet will provide funding opportunities for small projects to help establish these new research partnerships.
Cellular prion proteins, PrPc, have long been associated with a family of fatal neurodegenerative diseases called Transmissible spongiform encephalopathy (TSE), more recently PrPc have been linked to Alzheimer's disease. The network will build upon existing research into TSE's to advance understanding into the role PrPc plays in the development of age related and neurodegenerative diseases. In the case of the general public the achievement of the network objectives and advancement in the understanding of age related diseases would have a direct and beneficial effect. Advancement in diagnostic techniques and therapeutic tools would result in an increased life expectancy and standard of living for Alzheimer's patients. The benefits to the interest group stakeholders, for example the Alzheimer's Society are similar in that the development of such a network has the potential to progress research into the causes, cures and prevention of these conditions. Several interest groups have accepted invitations to sit on the PCBNet management committee, this will provide these groups the opportunity to help steer the focus of the network, the acceptance of these invitations illustrates that these groups recognise and appreciate the importance of such a network.
The potential of a network dedicated to the furthering the understanding of prion proteins has been acknowledged by industry representatives from Eli-Lilly and AstraZeneca, both world leading pharmaceutical companies and from smaller commercial partners AFChemPharm and Retrogenix. The benefit of the network to commercial partners is that it will provide an opportunity to collaborate with a multidisciplinary team of experts and potentially provides early access to non-confidential research results. As the UK population ages, age related diseases will become increasingly common as such the social and economic benefits to the UK in developing treatments for these conditions could be huge.
Organisations
- University of Sheffield (Lead Research Organisation)
- Amorfix Life Sciences Ltd (Collaboration)
- Eli Lilly & Company Ltd (Collaboration)
- University of California, San Francisco (Collaboration)
- Centre of Integrated Drug and Biomarker Discovery (Collaboration)
- Utrecht University (Collaboration)
- Retrogenix (Project Partner)
Publications
Thompson MJ
(2011)
2,4-diarylthiazole antiprion compounds as a novel structural class of antimalarial leads.
in Bioorganic & medicinal chemistry letters
Mohanty ST
(2012)
A small molecule modulator of prion protein increases human mesenchymal stem cell lifespan, ex vivo expansion, and engraftment to bone marrow in NOD/SCID mice.
in Stem cells (Dayton, Ohio)
Thompson MJ
(2011)
Discovery of 6-substituted indole-3-glyoxylamides as lead antiprion agents with enhanced cell line activity, improved microsomal stability and low toxicity.
in European journal of medicinal chemistry
Chen, B.
(2014)
Prion Chemical Biology: On the Road to Therapeutics?
in Curr Top Med Chem.
Thompson M
(2010)
Structure-Activity Relationship Refinement and Further Assessment of Indole-3-glyoxylamides as a Lead Series against Prion Disease
in ChemMedChem
Thompson MJ
(2012)
Synthesis and evaluation of 1-amino-6-halo-ß-carbolines as antimalarial and antiprion agents.
in ChemMedChem
Description | This network funding enables the community of prion and neurodegenerative diseases research coming together to share the knowledge and know-how, to provide small POC fundingto obtain preliminary data and to form larger consortium to apply for further funding. |
Exploitation Route | Further funding in the area will allow new diagonostics and therapeutics to be developed for clinic use. |
Sectors | Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology |
Description | The network activities promoted and contributed to the development of commercial products and intellectual property. |
First Year Of Impact | 2014 |
Sector | Healthcare |
Impact Types | Societal |
Description | EPSRC Theme Day |
Geographic Reach | National |
Policy Influence Type | Contribution to a national consultation/review |
Impact | The recommendation of the theme day reshaped the RU policy and priority on healthcare, especially in regenerative medicine field. |
Description | Stem Cells, Prion Proteins and Alzheimer's Diseases: A Prion Chemical Biology Network (PCBNet) |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Citation in other policy documents |
Impact | The network will seek to drive prion chemical biology research into two relatively new areas of relevance to the ageing society and in personalised medicine, building on the advances in understanding, skills and facilities developed in the study of transmissible spongiform encephalopathy (TSE) over recent years: 1)The normal physiological role of prion protein in the behaviour and function of stem cells and in embryonic development; 2)The role of prion protein in ageing and neurodegenerative diseases, e.g. Alzheimer's disease (AD) and TSE. The over arching objective of the proposed network is to enable the scientific community to expand its understanding of the role of prions in biology and to accelerate progress to new diagnostic and therapeutic tools for the improvement of human and animal health. |
URL | http://gtr.rcuk.ac.uk/projects?ref=EP%2FI037296%2F1 |
Description | Assessment of the Fanconi Anaemia pathway and its inhibition in Glioblatoma Multiforme |
Amount | £153,000 (GBP) |
Organisation | Yorkshire Cancer Research |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2014 |
End | 12/2016 |
Description | Assessment of the Fanconi Anaemia pathway and its inhibition in Glioblatoma Multiforme |
Amount | £66,000 (GBP) |
Organisation | Weston Park Hospital |
Department | Weston Park Hospital Cancer Charity |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2013 |
End | 12/2013 |
Description | Design and Synthesis of Pharmaceutically Relevant Chemical Entities |
Amount | £192,000 (GBP) |
Funding ID | 007548 |
Organisation | Innovate UK |
Sector | Public |
Country | United Kingdom |
Start | 09/2010 |
End | 09/2013 |
Description | Diagnostic and Drug Discovery Initiative for Alzheimer's Disease (D3i4AD) |
Amount | € 2,209,000 (EUR) |
Funding ID | 612347 |
Organisation | European Commission |
Department | Seventh Framework Programme (FP7) |
Sector | Public |
Country | European Union (EU) |
Start | 10/2014 |
End | 09/2018 |
Title | SMB cell line |
Description | It was made available to research groups interested. |
Type Of Material | Biological samples |
Year Produced | 2011 |
Provided To Others? | Yes |
Impact | It provides a tool to assess the antiprion activity of compounds. |
Title | Small molecule chemical probes |
Description | Small molecules that can enhance the proliferation of stem cells |
Type Of Material | Technology assay or reagent |
Year Produced | 2011 |
Provided To Others? | Yes |
Impact | The compounds are available to research community interested |
Title | Chemical compound library |
Description | It contains chemical compounds synthesised in my group. |
Type Of Material | Database/Collection of data |
Year Produced | 2010 |
Provided To Others? | Yes |
Impact | It has potential to be developed as novel therapeutics. |
Description | Assessment of DMPK properties of small molecule antiprion compounds in mice models |
Organisation | University of California, San Francisco |
Country | United States |
Sector | Academic/University |
PI Contribution | Preparation of small molecule antiprion compounds |
Collaborator Contribution | Assessment of DMPK properties of small molecule antiprion compounds in mice models |
Impact | Results to be published |
Start Year | 2013 |
Description | Development of new diagonistic tool for Alzheimer's disease |
Organisation | Centre of Integrated Drug and Biomarker Discovery |
Country | United Kingdom |
Sector | Public |
PI Contribution | Test copper chelating compounds in cellular models |
Collaborator Contribution | Design and synthesis of copper chelating compounds |
Impact | This has led to a large EU Marie Currie IAPP network grant (2.2 M Euor). |
Start Year | 2011 |
Description | Investigate the role of prion protein in Alzheimner's disease |
Organisation | Eli Lilly & Company Ltd |
Country | United Kingdom |
Sector | Private |
PI Contribution | know-how and 12 years experience in prion research field |
Collaborator Contribution | Strong track record in drug discovery in commercial sector |
Impact | successful studentship and EU grants |
Start Year | 2013 |
Description | Test and validation of the role of prion protein in Alzheimer's disease models |
Organisation | Amorfix Life Sciences Ltd |
Country | Canada |
Sector | Private |
PI Contribution | Design the epitope of antibody for Abeta amyloid protein |
Collaborator Contribution | Production of anti Abeta amyloid antibody |
Impact | A successful application of EU project |
Start Year | 2011 |
Description | small molecules that influence Prnp expression and differentiation potential of canine BM-MSCs |
Organisation | Utrecht University |
Department | Faculty of Veterinary Medicine |
Country | Netherlands |
Sector | Hospitals |
PI Contribution | Proof of concept validation of small molecules that influence Prnp expression and differentiation potential of canine BM-MSCs. |
Collaborator Contribution | Test the small molecules in canine BM-MSCs. |
Impact | Results to be published. |
Start Year | 2014 |
Title | INDOLE DERIVATIVES FOR THE STIMULATION OF STEM CELL PROLIFERATION |
Description | The present invention relates to indole derivatives of formula (I) and Formula (II) which possess potent antiprion activity and stem cell proliferative properties. The invention also relates to the use of such compounds to treat prion-related diseases and in stem cell therapies. |
IP Reference | WO2010139982 |
Protection | Patent granted |
Year Protection Granted | 2010 |
Licensed | No |
Impact | Novel indole compounds as regenerative medicine. |
Title | A pre-symptomatic blood test for Alzheimer's disease |
Description | A pre-symptomatic test to capture and measure the seeded aggregation of amlydoid beta peptides from clinical samples. It is used for detecting seeded protein aggregation in the brain, and have shown convincing results with Alzheimer fly and mice brain models. It can alsombe used to screen drugs against an ex-vivo biomarker for the seeded aggregation of Aß-peptide. This biomarker is thought to underpin the progression of the disease. |
Type | Diagnostic Tool - Non-Imaging |
Current Stage Of Development | Refinement. Non-clinical |
Year Development Stage Completed | 2013 |
Development Status | Under active development/distribution |
Impact | A new method for detecting seeded protein aggregation in the brain, and have shown convincing results with Alzheimer fly and mice brain models. There is currently no biomarker test that effectively quantifies the underlying disease activity in AD. The test will be used: 1). initially by the pharmaceutical industry as a novel biomarker that can provide a surrogate marker for disease activity 2). for clinical trials to stratify patients according to their risk of AD 3). by clinicians to enable early AD diagnosis and subsequent monitoring of disease evolution |
URL | http://www.floceleris.com/ |
Company Name | Floceleris |
Description | The PCBNet funding contributes to the product development of a spin out from one of the consortium, Floceleris, from Cambridge university headed by Dr. Damian Crowther. |
Year Established | 2013 |
Impact | Floceleris uses novel technology to detect the seeded protein aggregation that is thought to underpin the progression of diseases such as Alzheimer's. We expect our biomarker assay is useful for drug discovery, companion diagnosis and population screening. |
Website | http://www.floceleris.com/ |
Description | 9th IUPAC International Symposium on Biomolecular Chemistry |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | International conference. |
Year(s) Of Engagement Activity | 2012 |
Description | Prion 2012 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Raise public awareness and share scientific information. |
Year(s) Of Engagement Activity | 2012 |
Description | Royal Society of Chemistry Biological and Medicinal Chemistry Sector (BMCS) 2nd RSC Symposium on Chemical Biology for Drug Discovery 20th -21st of March 2012 AstraZeneca, Alderley Park, Macclesfield, UK |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Raise public awareness in stem cell, the role of prion protein and regenerative medicine. |
Year(s) Of Engagement Activity | 2012 |
Description | prion 2013 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Raise public awareness and share scientific information |
Year(s) Of Engagement Activity | 2013 |
Description | prion chemical biology article |
Form Of Engagement Activity | A magazine, newsletter or online publication |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | Raise public awareness |
Year(s) Of Engagement Activity | 2015 |