Realising Unmet Potential in Translational Medical Science at Durham
Lead Research Organisation:
Durham University
Department Name: UNLISTED
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
The Confidence in Concept scheme is a key part of MRC’s translational research strategy and provides annual awards to institutions, to be used flexibly to support the earliest stages of multiple translational research projects. The award can be used by the institution to support a number of preliminary-stage translational projects. The projects supported should aim to provide sufficient preliminary data to establish the viability of an approach –– before seeking more substantive funding. It is intended to accelerate the transition from discovery research to translational development projects by supporting preliminary work or feasibility studies to establish the viability of an approach.
Publications
Mina JGM
(2021)
Antileishmanial Chemotherapy through Clemastine Fumarate Mediated Inhibition of the Leishmania Inositol Phosphorylceramide Synthase.
in ACS infectious diseases
Rosa AC
(2022)
CNS-Sparing Histamine H3 Receptor Antagonist as a Candidate to Prevent the Diabetes-Associated Gastrointestinal Symptoms.
in Biomolecules
Obara I
(2019)
Histamine, histamine receptors, and neuropathic pain relief
in British Journal of Pharmacology
Alpizar-Sosa EA
(2022)
Genome deletions to overcome the directed loss of gene function in Leishmania.
in Frontiers in cellular and infection microbiology
Brittain WDG
(2020)
Synthesis of complex unnatural fluorine-containing amino acids.
in Journal of fluorine chemistry
Pohl E
(2020)
Classical pathways of gene regulation by retinoids.
in Methods in enzymology
Brittain WDG
(2019)
Tetrafluoropyridyl (TFP): a general phenol protecting group readily cleaved under mild conditions.
in Organic & biomolecular chemistry
Alpizar-Sosa EA
(2022)
Amphotericin B resistance in Leishmania mexicana: Alterations to sterol metabolism and oxidative stress response.
in PLoS neglected tropical diseases
Brittain WDG
(2020)
Protecting Group-Controlled Remote Regioselective Electrophilic Aromatic Halogenation Reactions.
in The Journal of organic chemistry
| Description | 'Raising Histamine for delirium: an opinion' Paul proposed a potential new pharmacological approach for the treatment and prevention of delirium. He explained that histamine plays a key role in modulating the characteristic features of delirium, providing a rationale for managing this poorly treated clinical condition by maintaining brain histamine levels during the day. While centrally-permeable H1 and H2 histamine receptor antagonist drugs have pro-delirium potential and should be used with care, he proposed that centrally-permeable pre-synaptic H3 histamine receptor antagonist drugs, which maintain steady brain histamine levels, may provide an exciting new and tractable strategy to combat delirium (a review article has just been accepted for publication based on this idea in the journal Frontiers in Pharmacology |
| Geographic Reach | National |
| Policy Influence Type | Influenced training of practitioners or researchers |
| Description | Deconvoluting the mode-of-action of novel anti-Chagas and anti-leishmanial compounds |
| Amount | £284,068 (GBP) |
| Funding ID | TC279 |
| Organisation | Tres Cantos Open Lab Foundation |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 03/2020 |
| End | 03/2023 |
| Description | Development of platforms to study transmembrane proteins - towards medical, agricultural and biotechnological benefits |
| Amount | £40,000 (GBP) |
| Organisation | São Paulo Research Foundation (FAPESP) |
| Sector | Public |
| Country | Brazil |
| Start | 12/2018 |
| End | 11/2021 |
| Description | Northern Accelerator |
| Amount | £49,200 (GBP) |
| Organisation | United Kingdom Research and Innovation |
| Department | Northern Accelerator |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 02/2020 |
| End | 06/2021 |
| Description | Patient-centric supramolecular formulations of new anti-leishmanial drugs for Indian Communities |
| Amount | £906,253 (GBP) |
| Funding ID | EP/T020490/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 03/2020 |
| End | 03/2022 |
| Title | CCDC 1856218: Experimental Crystal Structure Determination |
| Description | Related Article: William D. G. Brittain, Steven L. Cobb|2019|Org.Biomol.Chem.|17|2110|doi:10.1039/C8OB02899K |
| Type Of Material | Database/Collection of data |
| Year Produced | 2019 |
| Provided To Others? | Yes |
| URL | http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/ccdc.csd.cc209k0x&sid=DataCite |
| Title | CCDC 1856219: Experimental Crystal Structure Determination |
| Description | Related Article: William D. G. Brittain, Steven L. Cobb|2019|Org.Biomol.Chem.|17|2110|doi:10.1039/C8OB02899K |
| Type Of Material | Database/Collection of data |
| Year Produced | 2019 |
| Provided To Others? | Yes |
| URL | http://www.ccdc.cam.ac.uk/services/structure_request?id=doi:10.5517/ccdc.csd.cc209k1y&sid=DataCite |
| Description | A Screening Technology For Adverse Drug Reactivity Involving Cell Membranes |
| Organisation | GlaxoSmithKline (GSK) |
| Department | Neuroscience (GSK) |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | WP 1 Two new lipids have been successfully synthesised by organic synthesis. The synthesis of a further lipid is ongoing. Our probes are novel in their combination of photostability and chemical stability towards hydrolysis. WP2. Method validation: the new lipids have been incorporated into liposomes and their fluorescence properties determined. The effects of liposome composition have been examined and shown to influence probe properties. Our probes were demonstrated to have a high sensitivity towards changes in membrane composition and properties. This sensitivity, combined with the stability outlined form WP1, makes these probes unique. It was demonstrated that the liposome+probe system works in a 96 well (high throughput) format. WP3. Extension to known actives. Using the 96-well format, the fluorescence properties of a range of probe+liposome compositions have been examined in the presence of known drugs that are membrane-reactive. |
| Collaborator Contribution | The company provided expertise as well as materials. The aim is that they will be collaborators through to commercialisation. |
| Impact | Using this approach it was possible to identify probe/liposome combinations for which the probe response correlated with the known membrane reactivity of the drug in vivo. Our probes therefore have potential application for screening for potentially problematic drugs. The ability to screen in vitro at an early point in drug discovery is a key innovation from this work.This project has demonstrated the concept that lipid probes incorporated in to liposomes can be used to screen for chemical entities (drugs) that are likely to produce adverse toxicities. Unexpected or unanticipated drug reactivity in vivo is an ongoing problem during drug development that can lead to the failure of some lead compounds at a late stage in the development process. Detection of adverse chemical reactivity at an early stage in the drug development cycle has the potential to reduce costly failures both in terms of time and money but also increase patient safety. A funding application has been made to the MRC that includes the existing partner on the project (GSK) and new partnership with Medicines Discovery Catapult (MDC). The engagement with MDC provides support for the application, particularly with regard to screening human tissues for idiosyncratic toxicities. MDC involvement also provides a mechanism for the innovations from the MRC grant, and this CiC project, to be delivered to SMEs involved in drug discovery. GSK involvement provides key expertise on drug idiosyncratic effects and access to a broader range of chemical entities for which in vivo toxicities have been measured. [Footnote.] Further Funding: Application submitted to MRC (Jan 2020, Molecular and Cellular Medicine Board): Lipid Probes for Idiosyncratic Drug Responses, £636k, MRC ref: MR/V001531/1 |
| Start Year | 2019 |
| Description | Exploring the application of a breath-acetone sensor in the diagnosis and treatment of diabetic ketoacidosis in children in a clinical setting |
| Organisation | Royal Victoria Infirmary |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | Our research team has developed a sensor for the quantification of acetone in breath. We have tested the sensor on human volunteers. |
| Collaborator Contribution | In kind support by Dr Tim Cheetham (paediatric endocrinologist) on developing applications for the breath-acetone sensor and for funding applications. |
| Impact | An MRC Confidence in Concept award from Newcastle University, where Dr Tim Cheetham is a Reader in paediatric endocrinology. |
| Start Year | 2014 |
| Description | High-throughput screens for the discovery of selective retinoic acid receptor ligands |
| Organisation | High Force Research Ltd |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | (i) Recombinant protein expression of the three key targets RARs a, ß and ?. All three proteins were expressed, RARa and RAR? in high yields that allowed purification, biophysical characterisation and their use in high throughput (HTP) assays. (ii) Establishment of HTP screening of synthetic retinoids: The displacement assay using fluorescent synthetic retinoid was successfully formatted in 96-well plates. The proof-of-principles experiments with the Cellular Retinoid Assay Binding Protein 2 (CRABP2) as well RAR a and ? were successfully concluded. As part of this work package we also developed the computational procedures required for robust and reproducible data analysis. (iii) Application of the HTP assay to the retinoid library: Over 70 synthetic retinoids were tested and differential binding to RARa and ? was established. This allowed us to begin the detailed structure-activity relationship studies. |
| Collaborator Contribution | The collaborator provided some assays and will work with the university to scale up outputs. |
| Impact | In this project, we have demonstrated the validity and robustness of a new high-throughput assay for drug discovery with important biological targets, retinoic acid receptors-a (RARa) and RAR?. Retinoids are a class of endogenous molecules derived from Vitamin A, that control a wide range of cellular processes including differentiation, proliferation, apoptosis and homeostasis, by regulating transcriptional control in the cell nucleus. In spite of their importance, natural retinoids have limited therapeutic usage due to their inherent chemical instability and their broad range of biological functions. Numerous groups have developed synthetic retinoids but the key challenge remained to develop specific compounds for particular RAR subclasses to elicit a specific biological response, as a function of receptor specificity versus ligand structure. The high-throughput assay that we have developed enables the screening of potential retinoid drug libraries against each of the retinoic acid receptors, providing a direct insight into receptor binding specificity Further progress/ impact of the outcomes: Continuing the development of a robust and reproducible high-throughput assay is instrumental for the future development and in order to achieve higher expression levels of RARß a new set of expression constructs were designed and the future work of a postgraduate student will focus on the expression of RARß to complete the structure-activity relationship studies. We have created the Spin-out company RAR-M therapeutics in December 2019 with the aim to take the most promising compounds with neuroregenerative properties towards the treatment of Amyotrophic Lateral Sclerosis (ALS). This also forms the basis of a Wellcome Trust Innovator full application together with colleagues from Biosciences, Psychology and our partners at the University of Aberdeen. Spinout company created: RAR-M therapeutics Further Funding: Application submitted to Wellcome Trust Innovator Award, December 2019, £500k, Targeting ALS treatment through a novel Retinoic Acid Receptor- Modulatory approach |
| Start Year | 2019 |
| Description | IMTECH:UNICAMP |
| Organisation | State University of Campinas |
| Country | Brazil |
| Sector | Academic/University |
| PI Contribution | Facilitation and funding |
| Collaborator Contribution | Research |
| Impact | Not yet |
| Start Year | 2019 |
| Description | Validation of ZPL-8680871, a novel central nervous system-sparing histamine H3 receptor antagonist, for use in neuropathic pain |
| Organisation | Novartis |
| Department | Novartis Pharmaceuticals UK Ltd |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | The three scientific objectives of testing the i) therapeutic applicability of ZPL-8680871 in a pre-clinical model of neuropathic pain, (ii) the long-term efficacy of ZPL-8680871 after peripheral localized application, and (iii) ZPL-8680871 tolerability/lack of dependence properties were attained. We showed for the first time that ZPL-868087 had a significant and selective effect on attenuating mechanical hypersensitivity in a mouse model of neuropathic pain and moreover, localized peripheral administration of ZPL-868087 resulted in long-lasting (up to 72 h) alleviation of mechanical hypersensitivity in neuropathic mice, suggesting the potential for a unique long-term efficacy profile, which is highly desired to improve chronic neuropathic pain control. This analgesic effect was blocked by a peripherally administered selective H3R agonist, thus indicating the involvement of peripheral H3Rs in the mediation of this antinociceptive effect. |
| Collaborator Contribution | The company provided samples of the ZPL-8680871 used in the project as well as advice and support. |
| Impact | Project methodology and innovative approaches used (not multidosciplinary): Based on the mechanism(s) of injury-induced hypersensitivity, it is possible that ZPL-868087 targeted only a subpopulation of A delta fibres responding specifically to mechanical stimulation, where H3R was shown to be exclusively expressed. To further support the peripheral profile of ZPL-868087 and its therapeutic application, we showed that localized peripheral administration of ZPL-868087 resulted in long-lasting (up to 72 h) alleviation of mechanical hypersensitivity in neuropathic mice, suggesting a potential for a unique long-term efficacy profile, which is highly desired to improve chronic neuropathic pain control. In addition, the preclinical profile of ZPL-8680871 showed its high tolerability and suitability for oral dosing, thus further supporting the potential for ZPL-8680871 as a clinical strategy for improving neuropathic pain control. Three main mechanisms (AMPAR, NMDAR and mTOR) were explored and we have new preliminary evidence that mTOR signalling is involved in the long-term analgesic effects of ZPL-8680871. Further progress/ impact of the outcomes: Next steps for the project include developing a novel formulation and delivery system for ZPL-8680871, which has formed the basis of a MRC-DPFS application submitted in November 2019, led by Newcastle University, our collaborator on the project. [Footnote]. Further Funding: Application submitted to MRC DPFS (Outline Stage) Led by Newcastle £465k, Validation of a novel CNS-sparing histamine H3 receptor antagonist ZPL- 8680871 for peripheral delivery in pre-clinical models of neuropathic pain. Publication: Histamine, histamine receptors, and neuropathic pain relief. Obara I, Telezhkin V, Alrashdi I, Chazot PL. Br J Pharmacol. 2019 May 2. doi: 10.1111/bph.14696. |
| Start Year | 2019 |
| Title | Measurement of acetone in tidal breath |
| Description | A method by which to quantify acetone in breath in real time, direct from the subject, using laser spectroscopy. |
| IP Reference | UK Patent Application No. 2014270.9 |
| Protection | Patent application published |
| Year Protection Granted | 2021 |
| Licensed | No |
| Impact | The breath acetone sensor has been used to quantify acetone directly in the breath of human volunteers. |
| Title | Votucalis: Neuropathic pain |
| Description | Methods of treating neuropathic pain are provided. In particular, the invention provides a method for treating neuropathic pain related mechanical hypersensitivity (allodynia and hyperalgesia) and peripheral neuropathic pain (Renewed in 2020 for US coverage) and Press release Feb 1st 2021 for Investment for clinical development. |
| IP Reference | WO EP GB WO2019110825A1 |
| Protection | Patent granted |
| Year Protection Granted | 2019 |
| Licensed | No |
| Impact | https://www.globenewswire.com/news-release/2021/02/01/2167440/0/en/Akari-Therapeutics-Adds-Histamine-Inhibitor-Votucalis-to-Pipeline-to-treat-Neuropathic-Pain-and-Dermatological-Disease.html Akari Therapeutics Adds Histamine Inhibitor Votucalis to Pipeline to treat Neuropathic Pain and Dermatological Disease CNS-sparing histamine-inhibitor based approach for Neuropathic pain Invention registered in US 2020 |
| Company Name | Pepmotec |
| Description | Pepmotec produces novel peptides for pharmaceutical companies. |
| Year Established | 2019 |
| Impact | The company has a strong IP position (two patents granted in the US and EU/ UK) and we are currently looking for initial investment to setup a research lab. |
| Website | http://www.pepmotec.com/ |
| Company Name | Respiratone |
| Description | Respiratone develops a mobile acetone breath analyser. |
| Year Established | 2022 |
| Impact | at design and testing and manufacture stage |
| Website | http://www.respiratone.com/ |
| Description | Pain in Parkinsons |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Patients, carers and/or patient groups |
| Results and Impact | Presentation to Durham Parkinson's UK Branch. Traditional primary research presentation to Branch for 2019. This presentation was to inform members of new advances in Parkinson's Research. This talk described recent advances by our group in developing new ways to treat neuropathic pain (which affects 40% of Parkinson's patients). |
| Year(s) Of Engagement Activity | 2019 |
| Description | Presentation at regional industrial engagement event - NEPIC Technology Showcase Event 2019 |
| Form Of Engagement Activity | Participation in an activity, workshop or similar |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Industry/Business |
| Results and Impact | Dr Will Britain the recruited PDRA to the project presented our research to a range of academics, industrialist, and third party sector organizations at a regional workshop - NEPIC Technology Showcase Event 2019. The aim of the event was to allow academics in the North East of England to present their research to industrialist, and third party sector organizations with the aim of developing new collaborations for translational pathway development. |
| Year(s) Of Engagement Activity | 2019 |
| URL | https://www.nepic.co.uk/event/nepic-university-technology-showcase-event/ |
| Description | Science and a Pint - two locations |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | Coping with pain: pharmacology and beyond - Public debate - part of International Science and a Pint Week run in Durham and Middlesbrough. |
| Year(s) Of Engagement Activity | 2019 |