Realising Unmet Potential in Translational Medical Science at Durham

Lead Research Organisation: Durham University

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

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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 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 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 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
 
Company Name PEPMOTEC LIMITED 
Description Set up as a University spin-out in 2019. Based on the peptide technology platforms developed as part of an EPSRC first grant led by Steven Cobb (grant PI). 
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.
 
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