Confidence in Concept 2012 - University of Oxford
Lead Research Organisation:
University of Oxford
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.
Organisations
- University of Oxford (Lead Research Organisation)
- UNIVERSITY OF OXFORD (Collaboration)
- EVOTEC (Collaboration)
- Amgen Inc (Collaboration)
- Karolinska Institute (Collaboration)
- Lund University (Collaboration)
- F. Hoffmann-La Roche AG (Collaboration)
- Sealife Pharma (Collaboration)
- The Wellcome Trust Sanger Institute (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- IMPERIAL COLLEGE LONDON (Collaboration)
- AIDS Clinical Trials Group (ACTG) (Collaboration)
People |
ORCID iD |
Publications
Abboud MI
(2016)
Interaction of Avibactam with Class B Metallo-ß-Lactamases.
in Antimicrobial agents and chemotherapy
Abhari RE
(2017)
Effect of annealing on the mechanical properties and the degradation of electrospun polydioxanone filaments.
in Journal of the mechanical behavior of biomedical materials
Ali M
(2022)
T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes.
in Nature biotechnology
Allison TM
(2015)
Quantifying the stabilizing effects of protein-ligand interactions in the gas phase.
in Nature communications
Angelov P
(2012)
Biomimetic synthesis, antibacterial activity and structure-activity properties of the pyroglutamate core of oxazolomycin.
in Organic & biomolecular chemistry
Aoki Y
(2013)
Development of multiexon skipping antisense oligonucleotide therapy for Duchenne muscular dystrophy.
in BioMed research international
Baldwin MJ
(2016)
A survey on beliefs and attitudes of trainee surgeons towards placebo.
in BMC surgery
Bayliss LE
(2017)
The effect of patient age at intervention on risk of implant revision after total replacement of the hip or knee: a population-based cohort study.
in Lancet (London, England)
Booth CAG
(2018)
Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors.
in Cancer cell
| Description | Chairman of Committee for allogeneic transplantations and cell therapies, Karolinska University Hospital |
| Geographic Reach | National |
| Policy Influence Type | Membership of a guideline committee |
| Impact | Allogeneic transplantations and cell therapies. |
| Description | International Society for Stem Cell Research (ISSCR) McEwen Award for Innovation selection committee |
| Geographic Reach | Europe |
| Policy Influence Type | Membership of a guideline committee |
| Impact | International Society for Stem Cell Research (ISSCR) McEwen Award for Innovation selection committee |
| URL | http://www.isscr.org |
| Description | Member of Board of Center for Molecular Medicine, Karolinska Institutet |
| Geographic Reach | National |
| Policy Influence Type | Membership of a guideline committee |
| Impact | Member of Board of Center for Molecular Medicine, Karolinska Institutet |
| Description | Member of Board of Center of Excellence in Developmental Biology, Karolinska Institute |
| Geographic Reach | National |
| Policy Influence Type | Membership of a guideline committee |
| Impact | 2003-2008: Member of Board of Center of Excellence in Developmental Biology, Karolinska Institute (Director, Professor Urban Lendahl) |
| Description | A novel biomimetic tissue engineering scaffold for soft tissue repair (BioPatch) |
| Amount | £60,000 (GBP) |
| Funding ID | S8457 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 12/2013 |
| End | 08/2014 |
| Description | Acquisition of high parameter cell sorter, FACSymphony S6 to WIMM FACS Core Facility |
| Amount | £112,500 (GBP) |
| Funding ID | 0008760 |
| Organisation | University of Oxford |
| Department | John Fell Fund |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 08/2020 |
| End | 08/2021 |
| Description | Acquisition of high-end FACS cell sorter for WIMM FACS facility. |
| Amount | £50,000 (GBP) |
| Organisation | University of Oxford |
| Department | John Fell Fund |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 01/2014 |
| End | 12/2014 |
| Description | Butterfield Awards for UK-Japan Collaboration in Medicine and Health 2015 |
| Amount | £12,000 (GBP) |
| Organisation | The Great Britain Sasakawa Foundation |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 05/2015 |
| End | 04/2018 |
| Description | CIMED (Center for Innovative Medicine) Karolinska Institutet, individual project grant, Modeling of leukemic stem cells |
| Amount | 15,000,000 kr (SEK) |
| Organisation | Karolinska Institute |
| Sector | Academic/University |
| Country | Sweden |
| Start | |
| Description | Cellular, molecular and clinical surveillance of clonal hematopoiesis during aging |
| Amount | 6,000,000 kr (SEK) |
| Organisation | Karolinska Institute |
| Sector | Academic/University |
| Country | Sweden |
| Start | |
| Description | Characterisation and Inhibition of Carnitine Biosynthesis Oxygenases |
| Amount | £655,047 (GBP) |
| Funding ID | BB/L000121/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 02/2014 |
| End | 02/2017 |
| Description | Characterisation and targeting of myelodysplastic and leukemic stem cells |
| Amount | £247,340 (GBP) |
| Organisation | Leukaemia and Lymphoma Research |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 04/2014 |
| End | 04/2016 |
| Description | Characterization, surveillance and targeting of cancer stem cells |
| Amount | 45,250,000 kr (SEK) |
| Organisation | Knut and Alice Wallenberg Foundation |
| Sector | Private |
| Country | Sweden |
| Start | 07/2017 |
| End | 07/2021 |
| Description | Confidence in Concept Award (PI) |
| Amount | £87,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 05/2013 |
| End | 10/2014 |
| Description | Defining the physiology and therapeutic potential of oxygenases as signalling enzymes. |
| Amount | £1,599,721 (GBP) |
| Funding ID | 106244/Z/14/Z |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 09/2016 |
| End | 09/2022 |
| Description | Donation to support the Pilot study of Deep Brain Stimulation in Severe Enduring Anorexia Nervosa |
| Amount | £150,000 (GBP) |
| Organisation | Charles Wolfson Charitable Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 04/2016 |
| End | 03/2019 |
| Description | Duchenne UK translational research |
| Amount | £50,000 (GBP) |
| Organisation | Duchenne UK |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 02/2015 |
| End | 02/2018 |
| Description | European Commission EHVA H2020 |
| Amount | € 28,000,000 (EUR) |
| Funding ID | 681032 |
| Organisation | European Commission |
| Sector | Public |
| Country | European Union (EU) |
| Start | 01/2016 |
| End | 12/2020 |
| Description | Functional and metabolic optimisation of immunotherapy |
| Amount | £202,492 (GBP) |
| Organisation | Emerson Collective |
| Sector | Private |
| Country | United States |
| Start | |
| Description | Investigator award: Innate-like T cells and integration of host defence |
| Amount | £2,035,864 (GBP) |
| Funding ID | 222426/Z/21/Z |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 02/2022 |
| End | 01/2027 |
| Description | MRC |
| Amount | £1,750,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 05/2017 |
| End | 04/2022 |
| Description | MRC DCS |
| Amount | £1,700,000 (GBP) |
| Funding ID | MR/L00528X/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 11/2014 |
| End | 10/2017 |
| Description | MRC Senior Clinical Fellowship |
| Amount | £1,800,000 (GBP) |
| Funding ID | MR/L006588/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2014 |
| End | 09/2019 |
| Description | Modeling of leukemic stem cells at CIMED (Center for Innovative Medicine) Karolinska Institutet |
| Amount | 2,600,000 kr (SEK) |
| Organisation | Karolinska Institute |
| Sector | Academic/University |
| Country | Sweden |
| Start | |
| Description | Modeling of pediatric acute lymphoblastic leukemia by targeting of ETV6-RUNX1 to fetal progenitors |
| Amount | 1,500,000 kr (SEK) |
| Funding ID | PR2016-0047 |
| Organisation | Childhood Cancer Foundation |
| Sector | Public |
| Country | Sweden |
| Start | 01/2017 |
| End | 12/2020 |
| Description | Muscular Dystrophy Ireland 2014 |
| Amount | € 20,000 (EUR) |
| Organisation | Muscular Dystrophy Ireland |
| Sector | Charity/Non Profit |
| Country | Ireland |
| Start | 08/2014 |
| End | 07/2015 |
| Description | PepGen: Peptide platform |
| Amount | £68,000 (GBP) |
| Organisation | Charley's Fund |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | 06/2017 |
| End | 01/2019 |
| Description | Pfizer |
| Amount | £1,023,000 (GBP) |
| Funding ID | NA |
| Organisation | Pfizer Inc |
| Sector | Private |
| Country | United States |
| Start | 12/2014 |
| End | 11/2017 |
| Description | Professor/ Prize in Medicine 2015 |
| Amount | 10,000,000 kr (SEK) |
| Organisation | Torsten Söderberg Foundation |
| Sector | Academic/University |
| Country | Sweden |
| Start | 01/2016 |
| End | 12/2025 |
| Description | Proof of Concept |
| Amount | £111,924 (GBP) |
| Funding ID | 641317 |
| Organisation | European Research Council (ERC) |
| Sector | Public |
| Country | Belgium |
| Start | 03/2015 |
| End | 09/2016 |
| Description | Senior Investigator Award |
| Amount | £2,262,504 (GBP) |
| Funding ID | 104633/Z/14/Z |
| Organisation | Wellcome Trust |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 02/2015 |
| End | 02/2021 |
| Description | Swiss Anorexia Foundation : Biannual grant call : Additional funding for Pilot study of Deep Brain Stimulation for Severe Enduring Anorexia Nervosa |
| Amount | £115,000 (GBP) |
| Organisation | Swiss Anorexia Nervosa Foundation |
| Sector | Charity/Non Profit |
| Country | Global |
| Start | 04/2017 |
| End | 03/2019 |
| Description | The Bill and Melinda Gates Foundation project grant |
| Amount | $351,146 (USD) |
| Funding ID | OPP1113647 |
| Organisation | Bill and Melinda Gates Foundation |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | 09/2014 |
| End | 09/2016 |
| Description | The identification of small molecule agents that can induce selective differentiation of cancer stem like cells (CSLSs) to more benign states leading to anti-tumour activity in vivo |
| Amount | £3,118,483 (GBP) |
| Funding ID | R39746/CN001 |
| Organisation | Oxstem Limited |
| Sector | Private |
| Country | United Kingdom |
| Start | 05/2016 |
| End | 05/2019 |
| Description | Tobias Award |
| Amount | 10,000,000 kr (SEK) |
| Organisation | Tobias Foundation |
| Sector | Private |
| Country | Sweden |
| Start | |
| Description | University Challenge Seed Fund (UCSF) |
| Amount | £150,000 (GBP) |
| Organisation | University of Oxford |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 06/2016 |
| End | 06/2018 |
| Description | Unravelling the molecular and therapeutic targets in single del(5q) MDS stem and progenitor cells |
| Amount | £249,464 (GBP) |
| Funding ID | 17017 |
| Organisation | Bloodwise |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 01/2018 |
| End | 12/2019 |
| Description | Unveiling the identity and therapeutic targets of MLLAF9 pediatric leukemia stem cells |
| Amount | 1,000,000 kr (SEK) |
| Organisation | Swedish Childhood Cancer Foundation |
| Sector | Charity/Non Profit |
| Country | Sweden |
| Start | 01/2023 |
| End | 12/2024 |
| Title | UniDec |
| Description | Computer programme - deconvolutes mass spectra |
| Type Of Material | Improvements to research infrastructure |
| Year Produced | 2014 |
| Provided To Others? | Yes |
| Impact | Considerable uptake - more than 50 downloads |
| Description | AIDS Clinical Trials Group |
| Organisation | AIDS Clinical Trials Group (ACTG) |
| Country | United States |
| Sector | Public |
| PI Contribution | UK representative of US ACTG HIV Cure strategy committee. Role is to explore new treatment strategies and studies, and to explore potential funding options. |
| Collaborator Contribution | Monthly teleconferences to allow sharing of information and unpublished data to inform further research |
| Impact | Sharing of data - multidisciplinary - virology/immunology/epidemiology/mathematical modelliing |
| Start Year | 2016 |
| Description | Adam Mead |
| Organisation | University of Oxford |
| Department | Weatherall Institute of Molecular Medicine (WIMM) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Mouse models of normal and malignant hematopoiesis. |
| Collaborator Contribution | Molecular analysis of hematopoiesis. |
| Impact | Multiple high impact publications listed in outcome. |
| Start Year | 2008 |
| Description | Anna Katharina (Katja) Simon |
| Organisation | University of Oxford |
| Department | Weatherall Institute of Molecular Medicine (WIMM) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Hematopoietic characterization of mice deficient in autophagy pathways. |
| Collaborator Contribution | Mouse models of autophagy deficiency. |
| Impact | Multiple joint high impact publications, see list of publication outputs. |
| Start Year | 2006 |
| Description | Anthony (Tony) Green |
| Organisation | University of Cambridge |
| Department | Cambridge Institute for Medical Research (CIMR) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Hematopoietic characterization of mouse models of hematological malignancies. |
| Collaborator Contribution | Development and studies of mouse models of hematological malignancies. |
| Impact | Multiple collaborative publications, see publication output. |
| Start Year | 2006 |
| Description | Antibacterial bioassays |
| Organisation | Sealife Pharma |
| Country | Austria |
| Sector | Private |
| PI Contribution | Supply of new chemical entities |
| Collaborator Contribution | Supply of antibacterial bioassays |
| Impact | Data not finalised yet |
| Start Year | 2014 |
| Description | Ben Davis - biological chemistry |
| Organisation | University of Oxford |
| Department | Department of Chemistry |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We have designed projects in which synthetic glycans are used to mask surfaces of vaccine immunogens to re-focus their immunogenicity. We provide the designs and the protein to which the glycan are linked, then we carry out the immunological analysis. We have provided peptide sequences to which we wish to adduct reactive carbonyls, allowing us to test proof-of-concept for the immune activatingn properties of these peptides. The Davis group has carried out the modified peptide synthesis and quality control. |
| Collaborator Contribution | The Ben Davis group in Chemistry has been designing reactive synthetic glycans for conjugation to immunogens including influenza HA that we are using for immunological studies The Davis group enables us to adduct reactive carbonyls in a site-specific manner to peptides, and we are investigating this for use in proteins for the current BBSRC-funded project |
| Impact | The Davis group has helped us develop a chemical cross-linking protocol for improving vaccine antigen stability The Davis group has piloted the site-specific adduction of reactive carbonyl groups to peptides and proteins |
| Start Year | 2012 |
| Description | CHERUB Cooperative: Collaborative HIV Eradication of Reservoirs: UK BRC |
| Organisation | Imperial College London |
| Department | Department of Medicine |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | I am the chair of the CHERUB TSC, the scientific lead and overall co-PI. CHERUB infrastructure has been funded across all five CBRCs as part of a 5-way cooperative agreement |
| Collaborator Contribution | Academic, strategy and intellectual input |
| Impact | Initially funding from the NIHR CBRC renewal across all five CBRCS |
| Start Year | 2010 |
| Description | Claus Nerlov |
| Organisation | University of Oxford |
| Department | Weatherall Institute of Molecular Medicine (WIMM) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Stem and progenitor cell characterisation. |
| Collaborator Contribution | Mouse genetic models of normal and malignant hematopoiesis. |
| Impact | As listed in outcome multiple high impact joint publications. |
| Start Year | 2006 |
| Description | Dr John Frater: Curing HIV: Immune Targeting of the Latently-Infected Cell |
| Organisation | University of Oxford |
| Department | Nuffield Department of Clinical Medicine |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Our aim was (1) to assess the viral proteins both produced within the cell and expressed on the cell surface using MALDI-TOF-TOF mass spectrometry (2) to demonstrate recognition and killing of latently-infected cells using highly specific T cell receptors (TCRs) transduced into cytotoxic T cells and (3) to use soluble TCRs conjugated to fluorochromes to identify specific antigens present on the surface of latent cells using fluorescence microscopy. The objectives have been met in part, with some proof of principle data for all three, but of varying stages. The delay has been essentially due to the interest of a pharmaceutical company in the same reagents that our industry partner was donating to us. However for the three objectives (1) Enough cells of the 8E5 cell line which models HIV latency could be grown to allow mass spec analyses in the absence and presence of cellular activation. Preliminary evidence indicated that HIV peptides were being presented in this latent cell line. The next step is to enhance the peptide elution stage. (2) It was possible to transduce the T cell receptor into CD8+ve T cells and to transduce HLA A2 into target cells. We then have been able to show enhanced killing. Interestingly the drugs under investigation for use in HIV trials (HDAC inhibitors) resulted in decreased killing and we are currently investigating the extent to which HLA Class I is down-regulated. (3) We have changed the detection technique from microscopy to flow cytometry to enhance sensitivity. |
| Collaborator Contribution | Objective: to assess the viral proteins both produced within the cell and expressed on the cell surface using MALDI-TOF mass assymetry, |
| Impact | Further funding: An MRC Senior Fellowship to the PI, £1.78M has been awarded partly as a result of the preliminary data gained from the CiC award, and a Commonwealth Studentship has been awarded to allow a new DPhil to take the work on from next term. An MRC Developmental Clinical Study Award has been awarded to the CoI for a proof of concept trial towards a Cure for HIV for £1.99M. Uptake and translation: Results too preliminary for take up with industry beyond current engagement with Adaptimmune Ltd. The principle of immune targeting of the HIV reservoir has achieved clinical translation in the form of a randomised study of HDAC inhibitors plus vaccination commencing recruitment in 1st Quarter 2015 (MRC DCS award), the principles of which are guided by those in this award and on which the PI on this CiC award is a co-PI. Work continues in applying affinity adapted T cell receptors to HIV-infected target cells and further characterisation through Mass Spec and fluorescent microscopy. |
| Start Year | 2013 |
| Description | Dr Max Crispin: Antibody receptor refocusing: A technology for increasing the potency of therapeutic antibodies |
| Organisation | University of Oxford |
| Department | Department of Biochemistry |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We have tested the potential of EndoS technology in improving anti-cancer monoclonal efficacy. We successfully cloned and expressed the IgV region of TIM-4 and used this domain within a novel fluorescent adenoviral construct (Ad5-turboFP650, developed in our lab) to confirm PS binding ex-vivo using the human breast carcinoma cell line SKBr3 (Figure 1). We are now in the process of fusing this functional TIM-4 domain to IgG1 Fc in order to create an effector function competent (Fc-Fc?R) construct for EndoS testing. Once this construct is ready, we will test EndoS using the same adenoviral assay which contains an Fc-Fc?R engagement component. We have successfully expressed and isolated HER24D5/8 containing both normal (anti-HER24D5_8wt) and high mannose (anti-HER24D5_8HM) Fc glycosylation. The former is sensitive whilst the latter is resistant to EndoS mediated Fc-Fc?R disruption. Both of these antibodies recognise HER2 with near equivalent affinity as Herceptin (Genentech), the licensed variant of this monoclonal for use with HER2 positive breast cancer. We have established a technique for the large scale purification of fully active EndoS from E.coli. As a proof of concept, we have used this EndoS in conjunction with Herceptin using SKBr3 cells which overexpress HER2 (approximately 1 million copies per cell). Using our Ad5-turboFP650 assay we have demonstrated that EndoS pre-treatment effectively enhances Trastuzumab Fc?R engagement in the face of competition by irrelevant serum derived antibodies (Figure 4). Confirmation of this phenomenon is scheduled for anti-HER24D5_8wt and anti-HER24D5_8HM. |
| Collaborator Contribution | To test this technology |
| Impact | The impact of EndoS on the efficiency of anti-HER24D5_8's ability to elicit antibody dependent cellular cytotoxicity (ADCC) against SKBr3 cells in competition with irrelevant serum antibodies has also begun. Pre-clinical efficacy studies have been initiated with using a humanised mouse model, HU-Murine. Extrapolating from our ex-vivo assays we expect that in the presence of Endo S, the therapeutic efficacy of anti-HER24D5_8 will be significantly enhanced. The potential for administration of EndoS at time points coinciding with peak serum anti-HER24D5_8 levels will also be explored. |
| Start Year | 2013 |
| Description | Dr Radu Aricescu: A novel diagnostic method for autoimmune disorders based on cell-derived vesicle microarrays |
| Organisation | University of Oxford |
| Department | Nuffield Department of Clinical Medicine |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | The aim of this project was to (1) Establish an efficient, reproducible and easy to scale-up procedure to generate cell-membrane derived outside-out vesicle preparations stable for long-term storage at 4C or, if possible, even dried, (2) Demonstrate that such vesicles are suitable for detection of autoantibodies in routine diagnostics. This will build on our successful preliminary work on AQP4 (shown below) and include known autoimmune targets such as glutamate, GABAB and glycine receptors, as well as other surface proteins (LGI1, CASPR2) and (3) Develop a procedure to improve immobilization of the vesicles displaying proteins of interest, using in-vivo biotinylation and streptavidin-coated slides or other substrates (i.e. membranes for potential dip-stick development). |
| Collaborator Contribution | . |
| Impact | Vesicle production from Aquaporin-4 (AQ4) transfected HEK cells has been improved and relative large preparations of membrane vesicles produced, suitable for 100-200 assays. Immuno-assay with AQ4 vesicles were optimised allowing blind screening of 100 patient sera and controls with very good correlation with diagnostic cell-based assay (major project goal achieved). Myelin Oligodendrocyte Glycoprotein (MOG) vesicle is in production for use in immuno-assay with MOG vesicles. Cloning of other neuronal receptor targets for use in the vesicle immuno-assays is on-going. Construction and validation of "AviFlag" tagging for binding to streptavidin was achieved (major project goal achieved) and we are establishing use of vesicles in a Streptavidin-coated micro-array system. A patent was filed in June 2014. The CiC project funding was used to successfully demonstrate exemplification of concept that has been included in the filing. Project will be launched to coincide with publication paper. |
| Start Year | 2013 |
| Description | Dr Rebecca Park: Hungry for reward: a translational study of brain processes underpinning Anorexia Nervosa |
| Organisation | University of Oxford |
| Department | Department of Psychiatry |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Severe longstanding Anorexia Nervosa has the highest mortality of any psychiatric disorder and is one of the most challenging and expensive to manage, with a major paucity of effective treatments. The broad aim of this project was to map the neural mechanisms underpinning aberrant reward in Anorexia Nervosa (AN), and to translate this understanding into the development of a novel neuroscience-based treatment. It combines an experimental strategy with complementary forms of cutting-edge neuroimaging including DTI, fMRI and MEG (studies 1-4). These will be augmentative in identifying optimal targets for intervention for severe AN using Deep Brain Stimulation (DBS) (study 5) on a single case. Analysis of resting state and task based fMRI data (studies 2 and 4) is underway. Preliminary findings of fMRI task and resting state data will be presented at the Eating Disorders Research Society in Sand Diego, October 2014. Study 5 is the first Pilot study of DBS for AN in the UK; the operation completed in April 2014 and now in data collection phase of psychiatric, neuropsychological and neuroimaging follow-up, and ethical sub-study. |
| Collaborator Contribution | To investigate key brain areas involved in reward processing-hedonic appraisal (liking) incentive salience (wanting) and learning and their interaction with cognitive control process, in order to define optimal targets for effective intervention in severe AN |
| Impact | Multimodal imaging data of AN including fMRI and MEG will be a unique data set and when combined with fMRI of major impact in the field. In collaboration with data analysis with Dr Mark Woolrich and Kia Nobre at OHBA -who have recently been awarded a programme grant to better develop and integrate multimodal imaging data- we are in an excellent position to lead on advancing understanding of neural basis of AN to aid treatment target development. Positive results from pioneering treatment development of DBS could thus be a game changing for the treatment of severe AN, potentially saving lives in addition to saving substantial sums of healthcare funding. Ethical considerations are however complex and of major importance, warranting ethical study in tandem. Dr Park sent the future grant outline derived from this pilot MRC CIC data to head of neurosciences and head of mental health at the MRC and discussed it with them in June 2014. They are encouraging submission of a project grant to further this work and we expect to submit in January 2015. Co-applicant Professor Aziz has also applied to the Charles Wolfson Charitable Trust for a grant. Medtronic have donated 3 stimulator systems of which one has been implanted and St. Judes have donated one for this study. Clinical translation is immediately apparent- as the DBS pilot study is registered on open access clinical trials. We have had enquiries and requests to participate from all over the UK, Europe (Germany) and the USA. At present we have ethical approval for 2 further cases but have not yet secured the funding. |
| Start Year | 2013 |
| Description | Dr Ruth Muschel: Hedgehog Signalling as a Biomarker for Prostate Cancer Prognosis |
| Organisation | University of Oxford |
| Department | Department of Oncology |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Several biomarker studies designed to explore Hedgehog (Hh) signalling within distinct prostate cancer types or therapy groups have been completed. A cohort of 177 patients with pathological evidence of prostate cancer ranging from Gleason score 6 to Gleason score 9 (Gleason score is a known indicator of prostate cancer severity) has been generated. In addition, 60 transurethral resections of prostate were included (as a benign control) as well as 3 cell lines (PC3, LnCAP, RWPE). This is a post-surgical cohort where cancer patients underwent radical prostatectomy. About two third of the patients progressed to cure whilst the remaining patients required salvage radiotherapy or hormone treatment upon biochemical (PSA) relapse. This tumour tissue microarray is referred to as the Oxford Surgical TMA (OS-TMA). A further post-surgical cohort, taken from patients in Belgium, was also made. These patients (N=75) presented with advanced prostate tumours. This cohort is particularly interesting as nearly one half of its constituents featured primary tumours that metastasized to the lymph nodes following surgical intermission. The preliminary conclusions suggest that Hh pathway proteins may contribute to the advancement/severity of prostate cancer and that their expression potentially affects patient outcome following surgical intervention. The first post-surgical TMA was sliced and stained for 8 different proteins. 7/8 proteins tested showed significantly altered (+ or -) staining in cancer versus benign tissues. High epithelial staining intensity of 3 proteins (GLI1, SMO and SHH) tested on the OS-TMA were significantly associated with higher Gleason scores. Each protein is associated with an "activated" Hh pathway. Thus, the epithelial expression of Hh proteins GLI1, SMO, and SHH may contribute to relapse as a factor of their association with Gleason score. However, this hypothesis needs to be further validated. |
| Collaborator Contribution | To evaluate tissue samples from three distinct patient cohorts to identify in Hh protein expression or signalling within cancerous prostates. |
| Impact | From these studies, it may eventually be possible to organize the most promising cancer markers into an expression array that could be useful as a predictive tool, or signature, for cancer aggressiveness. Thus, if Hh proves to be an important factor in prostate cancer severity, inhibitors against the pathway may be conducted. The use of anti-Hh drug adjuvant to radiotherapy is of particular interest. If Hh proves to be prognostic for prostate cancer severity, and laboratory inhibitors efficacious against the pathway, a clinical trial may proceed. In addition, the use of anti-Hh drug adjuvant to other chemotherapies or to radiotherapy would be of interest. Intellectual property: The The OX-TMA is the property of the University of Oxford. |
| Start Year | 2013 |
| Description | Dr Tudor Fulga: Rewiring cellular behaviour using miRNA-responsive synthetic devices |
| Organisation | University of Oxford |
| Department | Radcliffe Department of Medicine |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Cellular reprogramming using synthetic gene networks offers much promise for advancing scientific and therapeutic innovation. MicroRNA expression patterns provide a unique signature differentiating cells based on type as well as physiological state (including disease state) and could form an ideal input for such systems. To test this concept, we have constructed a prototype ribozyme-based controller containing a sensor/actuator and effector module, which can couple miRNA activity with the induction of GFP expression. Our preliminary experiments revealed that such a synthetic classifier could be activated in mammalian cells and in principle its activity can be modulated in the presence or absence of a specific input miRNA. We propose to expand this conceptual framework and showcase the potential of these logic function classifiers to enable user-regulated actuation of cellular behaviour. Ultimately, we plan to apply this strategy to engineer a prototype miRNA-responsive device for the detection of virally infected cells based on the digital presence or absence of exogenous viral miRNAs. |
| Collaborator Contribution | Optimise the ON:OFF ratio of a prototype miRNA-responsive device |
| Impact | We have established a strategic collaboration with the company Eukarys SAS in order to make use of their patented C3P3 technology, consisting of a chimeric enzyme capable of producing capped mRNA transcripts from a cytoplasmic plasmid. Discussions with ISIS innovation were promising and they indicated a desire to patent this work. The recommendation is however that we consider patent application only immediately before publication. The next step in this project will involve coupling allosteric ribozyme activity to an output apoptotic response. This will be facilitated both by the generation of new allosteric ribozymes demonstrating superior ON:OFF rates (from our in vitro evolution experiments) as well as the rational tuning of pro-apoptotic proteins by mutagenesis. Once validated, these circuits will be tested in a cell culture model of EBV infection to demonstrate their ability to detect specific EBV miRNA inputs and in response activate the apoptotic pathway. In order to construct circuits of higher complexity we plan to multiplex allosteric ribozymes, responsive to different input miRNAs into the 3' UTR of a single output protein. In addition to the theoretically enhanced ON:OFF rate, these multi-input logic gates should be capable of detecting the subtle alterations in miRNA expression levels often associated with human disease such as cancer, therefore making them susceptible to specific targeting using our devices. |
| Start Year | 2013 |
| Description | Elli Papaemmanuil |
| Organisation | The Wellcome Trust Sanger Institute |
| Country | United Kingdom |
| Sector | Charity/Non Profit |
| PI Contribution | MDS stem cells for sequencing for targeted mutations. |
| Collaborator Contribution | Expertise in exome sequencing. |
| Impact | Key for publication Woll et al, Cancer Cell, 2014. |
| Start Year | 2010 |
| Description | Eva Hellström Lindberg |
| Organisation | Karolinska Institute |
| Country | Sweden |
| Sector | Academic/University |
| PI Contribution | Studies of MDS stem and progenitor cell biology. |
| Collaborator Contribution | Clinical expert on MDS. |
| Impact | Multiple high impact publications listed in outcome. |
| Start Year | 2006 |
| Description | Industrial collaboration |
| Organisation | Evotec |
| Country | Germany |
| Sector | Private |
| PI Contribution | Supply of new chemical entities |
| Collaborator Contribution | Supply of bioassay and expertise |
| Impact | No finalised outcomes yet |
| Start Year | 2014 |
| Description | Industry Visitor |
| Organisation | Amgen Inc |
| Country | United States |
| Sector | Private |
| PI Contribution | Study of membrane proteins and ligand binding using approaches developed in laboratory. |
| Collaborator Contribution | Contacts in industry |
| Impact | Invitation to speak at Amgen |
| Start Year | 2014 |
| Description | Investigating immune-cancer interactions in multiple myeloma |
| Organisation | University of Oxford |
| Department | Radcliffe Department of Medicine |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | we investigate by single cell techniques such as mass cytometry and single cell sequencing the immune and cancer environment of human bone marrow samples from the multiple myeloma clinic. |
| Collaborator Contribution | Our clinical colleagues provide bone marrow and blood samples from patients. These are either biobanked samples or from ongoing, longitudinal studies. |
| Impact | Together we have setup the Oxford Centre for translational myeloma research. This includes Oxford PIs involved in basic and clinical myeloma research (eg drug discovery, basic cell biology, experimental medicine). We aim to set up a national network to combine the different strengths and skillsets in myeloma research in the UK. This also includes now close links to Myeloma UK, who are on our advisory board and steering committee. |
| Start Year | 2016 |
| Description | Marella de Bruijn |
| Organisation | University of Oxford |
| Department | Weatherall Institute of Molecular Medicine (WIMM) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Mouse Models for stem and progenitor biology. |
| Collaborator Contribution | Expertise in mouse developmental hematopoiesis. |
| Impact | Several high impact joint publications, as specified in publication output. |
| Start Year | 2010 |
| Description | Paresh Vyas |
| Organisation | University of Oxford |
| Department | Weatherall Institute of Molecular Medicine (WIMM) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | In vitro and in vivo assays for normal and malignant human hematopoiesis. |
| Collaborator Contribution | Clinical and genetic expertise in MDS and AML. |
| Impact | Several joint publications including Goardon et al, Cancer Cell 2010; Tehranchi et al, NEJM 2010; Woll et al, Cancer Cell 2014, Giustacchini et al, Nature Med 2017 |
| Start Year | 2008 |
| Description | Peter Campbell |
| Organisation | The Wellcome Trust Sanger Institute |
| Country | United Kingdom |
| Sector | Charity/Non Profit |
| PI Contribution | - |
| Collaborator Contribution | - |
| Impact | Key for 2014 publication in Cancer Cell, Woll et al. |
| Start Year | 2006 |
| Description | Professor Adrian Hill and Dr Irina Redchenko: Pre-clinical efficacy evaluation of the novel vaccine for prostate cancer |
| Organisation | University of Oxford |
| Department | Nuffield Department of Clinical Medicine |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | A vaccination platform based on a combination of two viral vectors encoding the same prostate cancer antigen has been studied to determine whether it can achieve cancer-protective immune response in a prostate cancer mouse model. Recombinant viral vectors, a simian adenovirus, ChAdOx1, and pox virus, MVA, expressing prostate-associated antigens PAP, PSCA, PSMA, STEAP1 and 5T4 have been constructed. The immunogenicity of those vectors delivered in a prime boost vaccination regime has been evaluated in the wild type C57BL/6 mice. The vaccine prophylactic and therapeutic efficacy has been tested in a tumour transplantation model. The vaccine therapeutic efficacy has been tested in in the transgenic adenocarcinoma of mouse prostate model (TRAMP). A strong T cell immune response has been generated against one of the tested antigens following vaccination with the vectors encoding this antigen. The induced immune response has been modestly protective in wild type C57BL/6 mice and TRAMP mice. |
| Collaborator Contribution | Objective: to evaluate a novel vaccination strategy as an immunotherapy for prostate cancer |
| Impact | Further Funding: EC project Improving Prostate Cancer Outcome with Vectored Vaccines (IMPROVE). The value is €6M for 4 years across 5 European partners. The project includes funding for Phase I and Phase II clinical trials and further vaccine development to identify new vaccine targets and increase immunogenicity and efficacy. Uptake and translation: Phase I and II clinical trials have been funded. Potential collaborations with pharmaceutical companies in clinical development are underway. |
| Start Year | 2013 |
| Description | Professor Andrew Carr: A novel biomimetic tissue engineering scaffold for soft tissue repair (BioPatch) |
| Organisation | University of Oxford |
| Department | Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Diseases (NDORMS) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Age related soft tissue degeneration and inflammation (tendon, muscle and cartilage) affects around 35% of the population causing significant pain, loss of function and time off work. Rates of shoulder surgery for tendinopathy and tendon tear have increased over the past ten years by around 750% in the USA and the UK. But, between 20% and 90% of tendon repairs fail within the first few months after surgery. This project has made significant progress to producing a safe, effective and cost effective tissue repair patch that can be used to enhance and improve the success of tendon repair surgery. A novel, degradable, woven and electrospun patch prototype has been developed, characterised and tested utilising in vitro tools and primary tendon-derived cells, showing exceptional biocompatibility, improved cell attachment and that cells could migrate across the patch towards a chemo-attractant. Proof of concept was achieved in vitro by (a) using human tendon-derived cells as a model system to evaluate the patch and (b) implantation in a tendon injury model in rats. Safety data was gathered in vitro and in vivo, including cytotoxicity, tissue reaction and implant integrity. The electro-spinning and weaving processes were enhanced to enable the production of laminated patches as well as improved homogeneity. The quality of the tendon-bone repair in the rat was carried out with and without the patch in terms of mechanical properties of the tendon to bone insertion has been assessed. There is a potential for using this scaffold in the surgical repair of interfaces such as the tendon insertion in the rotator cuff, in conjunction with growth factors and / or stem cells. (Hakimi et al 2012). |
| Collaborator Contribution | Primary objective: refine the prototype soft tissue patch. Prove biocomplatibility and efficacy and test pre-clinically in vitro and in vivo. |
| Impact | Further progress: The study of the migration of stem cells and tenocytes through laminated patches in vitro has been achieved. The additional effect of growth factors, platelet rich plasma and stem cells on tenocyte growth and differentiation have been characterised. Characterisation of the interaction between the material and tendon-derived cells throughout the degradation of the patch in vitro and in vivo is underway. Manufacturing facility upscale is underway. Testing of the effective of sterilisation on material properties is planned. Clean room manufacture and Phase I human clinical trial is also planned. IP: Two patents filed in September 2013. Examined in March 2014 without undue concern raised. Further funding: £40k awarded in June 2014 from the Oxford University Hospital's Innovation Challenge Competition. Uptake and translation: The Oxford BRC will upscale production within the University/NHS partnership and produce the implant in a clean room for human use. One this has been successfully achieved, a Phase II clinical trial is planned. Potential industry partner has approached to discuss licensing but currently the plan is to upscale manufacturing internally and progress to clinical trial without external investment. |
| Start Year | 2013 |
| Description | Professor Christopher Schofield: Potential for Translational Effects of BBOX Inhibition |
| Organisation | University of Oxford |
| Department | Department of Chemistry |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | BBOX is a 2OG-dependent oxygenase that catalyses the final step in the biosynthesis of carnitine from Ne-trimethyllysine in animals. Carnitine if important in fatty acid metabolism, enabling transport of fatty acids in mitochondria. There is evidence that BBOX is a viable target for small molecule inhibition for the treatment of cardiovascular disease. In this project selective BBOX inhibitors were identified, assays suitable for HTS and cell-based screens were optimised, the solution of crystal structures of BBOX-inhibitor complexes revealed unprecedented mechanism of action |
| Collaborator Contribution | Objective: to identify potent and selective inhibitors for BBOX |
| Impact | Further progress: The funding has enabled multiple publications and a potent application. In an unexpected development the screening methods developed were also applied to an antibiotic resistance enzyme. The resultant publication Angewandte Chemie Int. Ed., 2014, 53(12), 3129-3133 made the front cover of Angewandte Chemie, has attracted considerable attention. IP: A patent has been filed. Further funding: Preliminary results and information from this project was the basis of a successful BBSRC grant value £660k to characterise carnitine biosynthesis enzymes and make inhibitors. Uptake and translation: The work enabled the development of assays that have been used in the development and predicting of selective oxygenase inhibitors. The work has helped to enable an IMI project on screening for inhibitors of a human oxygenase. We are also collaborating with a major pharmaceutical company on aspects of the work. |
| Start Year | 2013 |
| Description | Professor Dame Carol Robinson: A new way of exploring drug and lipid binding to membrane protein complexes |
| Organisation | University of Oxford |
| Department | Department of Chemistry |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | The aim of this project was to exploit the use of ion mobility mass spectrometry for drug discovery by identifying new detergents for introducing membrane complexes into the gas phase; to fine-tune our mass spectrometry approach to report on the effects of drug binding on membrane protein complex stability and folding; to contribute to the development of a robust method for assaying drug binding to membrane proteins. We were successful in expressing and purifying a number of membrane proteins using different protocols and different detergents optimized for mass spectrometry. We completed an investigating MS and solution conditions that preserve the complex as close to its native fold state as possible. This proved more challenging since many detergents perturb the native state of the protein. Lipidic environments for studying membrane proteins were employed - an important development for GPCRs which are often oligomeric in the presence of specific lipids. The gas phase unfolding method applied to membrane proteins is unique in the world and has enabled us to gain the first insights into lipid binding to membrane proteins. These developments were necessary to pave the way for the more difficult case of drug binding to membrane proteins. The novel methodology was reported in Nature this year and featured on the front cover of the journal. (Laganowsky et al Nature 510: 172, 2014). |
| Collaborator Contribution | To exploit the use of ion mobility mass spectrometry for drug discovery by identifying new detergents for introducing membrane complexes into the gas phase |
| Impact | Further Progress: This publication generated considerable interest from major pharma resulting in a number of key collaborations with Roche, Amgen and Genentech. IP: Two patents have been filed one previously protecting the idea to use this methodology for membrane protein drug discovery the other relating to the discovery of detergents that maintain the native state of the membrane protein such that unfolding can ensue. Further Funding: The PI obtained a senior investigator award from the Wellcome Trust based on the proof of concept data form this project. The next steps from the CiC project represented one of the five streams of research proposed in the Wellcome Trust project. Funding to support this stream of work totals to date: WT £2.2million, Roche £25K, ONT £25K. Uptake and translation: The PI is has hosted a collaboration with an academic visitor from Roche studying membrane proteins and ligand binding using our unique approaches. Two other pharmaceutical companies are keen to explore the technology, one has requested an in-house example and is considering funding for personnel, the other have also organised a visitor to observe the experiment in action. |
| Start Year | 2013 |
| Description | Professor Katherine Vallis: Quantitative Autoradiography at Ultra-High Spatial Resolution: Demonstration of Applications |
| Organisation | University of Oxford |
| Department | Department of Oncology |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | The central objective was to use ultra-high spatial resolution photoresists as autoradiography substrates to enable microdosimetric analyses of targeted radiotherapy agents. The initial motivation for this work was optimizing the detection of Auger electron-emitting radionuclides used for therapy, but the technique has since been extended in the detection of alpha-particles. Work underpinning the (1) cryo-tomography and enhanced spatial resolution and (2) correlating radionuclide distribution with DNA damage is still continuing with results to date recently presented at the Association of Radiation Research (ARR) and the Society of Nuclear Medicine and Molecular Imaging (SNMMI) annual meetings. The method has been extended in the detection of alpha and the results have been published in two recent papers |
| Collaborator Contribution | The overall aim is to strengthen the credentials of the method by demonstration of applications, and thereby secure funding for further development. |
| Impact | Further funding: We secured funding for an EPSRC studentship. The candidate, Georgina Royal has successfully defended her transfer and is now in her second year as a PhD student. Her thesis expands on the use of photoresists as a dosimetric tool for molecularly targeted radionuclide therapeutics. The proof of concept work funded within the CiC work will serve as the basis of an application for a programme grant for Dr. Nadia Falzone. Uptake and translation: We had preliminary discussion with a pharmaceutical company regarding possible application of this technique to alpha-emitting radiopharmaceuticals. |
| Start Year | 2013 |
| Description | Professor Mark Moloney: New generation antibacterial agents |
| Organisation | University of Oxford |
| Department | Department of Chemistry |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Using natural products as inspiration, new series of chemical compounds have been synthesised and evaluated for their antibacterial activity, providing access to three structurally unprecedented classes of compounds which are active in vitro predominantly against Gram positive, but also some Gram negative, strains. This work has provided a good understanding of the structural basis for this activity, enabled the development of a pharmacophoric model, and established the mode of action, which is against the unusual target, UPPS; IP for this work has been secured. Some compounds are active against UPSS and RNAP, and this offers significant advantage for the design of potent inhibitors. Work is currently underway to obtain detailed protein-inhibitor structural information by crystallographic protein analysis (with OPPF). Critically, these systems have never used therapeutically and therefore have not been widely dispersed amongst human and animal populations, so resistance might be expected to evolve more slowly. The next stage, funded as part of the MRC CiC programme, was to optimise in a three way simultaneous study, synthesis, phenotypic activity and plasma protein binding. This funding opportunity was also used to scope an entirely novel antibacterial delivery strategy. |
| Collaborator Contribution | To optimise in a three way simultaneous study, synthesis, phenotypic activity and plasma protein binding, in order to successfully achieve in vivo activity |
| Impact | Further progress: A second CiC award has been given for this stream of activity. See CiC 26. IP: The data from this work will provide additional supporting data for two patents currently in prosecution. Further funding: MRC DPFS applied for (Sep 2014) and the results from this work will also be used to provide preliminary data for an MRC AMR Innovation Grant planned for January 2015. Support by this programme has assisted the establishment of Antibacterial Discovery-UK, a network of scientists interested in the development of next generation antibacterials, and able to offer contributing expertise. Currently in the process of being expanding globally. Funding for this network will be applied for from an MRC AR Theme 2 Grant. |
| Start Year | 2013 |
| Description | Professor Matthew Wood: Development of exon skipping therapy for Duchenne muscular dystrophy |
| Organisation | University of Oxford |
| Department | Department of Physiology, Anatomy and Genetics |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | The aim of this project was to identify the minimum combinatorial requirements for multi-exon skipping oligonucleotides therapy for Duchenne muscular dystrophy (DMD). The long-term goal of this project is to combine this approach with the second generation peptide conjugated oligonucleotides that are currently being developed with Wellcome Trust Health Innovation Challenge Fund support, in order to develop a high efficiency generalised exon skipping approach to treat all DMD patients. We found that minimal spontaneous exons 45-55 skipping of the Dmd gene at low frequency in mouse C2C12 myotubes, which can be explained by the order and the timing of dystrophin intron removal. Secondly, we confirmed the minimum combinatorial requirements using three oligonucleotides which can enhance exon 45-55 skipping in mouse C2C12 myotubes. Thirdly, we started a new collaboration with Dr. Yokota's group, Alberta University, Canada. We are testing the efficacy of exon 45-55 skipping using sequences of oligonucleotides in human rhabdomyosarcoma cell lines and human primary myoblast cells.We are going to synthesize peptide conjugated oligonucleotides with optimized sequences and test their efficacy in human DMD primary myoblast cells carrying exon 46-51 deletions. The novelty of this work is to develop a multi-exon skipping oligonucleotides therapy for DMD with the minimum combinatorial requirements of oligonucleotides. As a next step, we plan to combine this approach with the second generation peptide conjugated oligonucleotides and to develop a novel multi-exon skipping approach high efficiency for all DMD patients. |
| Collaborator Contribution | To identify the minimum combinatorial requirements for multi-exon skipping AO therapy for DMD |
| Impact | Further progress: This work is likely to lead to publications in high impact, peer-reviewed journals, patents of resulting technology/candidate drugs for inducing skipping of exons 45-55 in DMD patients, leading to options for co-development with industrial partners in the future. This success will allow an application for a translational award to the Medical Research Council or the Wellcome Trust to further develop a generalized multiexon skipping targeting the whole exons 45-55 region of the human DMD gene which could enable the treatment of a large proportion of DMD boys. IP: N/A Further funding: Following this work, we have been successfully awarded a grant from Muscular Dystrophy Ireland in 2014 for €20,000. Uptake and translation: We anticipate interest from drug companies in this new technology and anticipate our exon skipping therapeutic agents will receive regulatory approval for use in DMD in the near future. |
| Start Year | 2013 |
| Description | Professor Paul Klenerman: A novel therapeutic approach for Hepatitis B virus |
| Organisation | University of Oxford |
| Department | Nuffield Department of Clinical Medicine |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Hepatitis B Virus (HBV) is a major cause of liver disease and cancer, affecting 300 million people. Treatments exist but are typically only partially effective. Progress has been made to develop a new treatment approach based on novel small molecules. The TGF-? family member BMP-6 has been tested for antiviral activity against HBV in a tissue culture system using the HepaRG hepatocyte cell line as a model for HBV infection. The related compound Activin A is a better inhibitor of HBV infection in cell culture systems. Genes involved in the TGF-? superfamily seem to be closely involved in triggering an antiviral response in hepatocytes infected with HBV. The specific pathway for this antiviral mechanism remains to be fully identified - both the signalling arm and the effector arm. However this project, involving qRT PCR and microarray analysis, show that innate immune response genes classically linked to the interferon pathway likely play a vital role and are being upregulated in response to Activin A. Activin A shows potential as a combined antiviral drug and can either complement or perhaps supplement IFNa or directly acting antivirals, both of which are imperfect therapies. |
| Collaborator Contribution | To define the antiviral activity of BMP6 in vitro against HBV |
| Impact | The RNAseq data analysis on HepaRG cells treated with Activin A will be completed to understand the impact of this compound on total RNA expression and compare it with the already obtained data from microarray analysis. This will help the understanding of the mechanism by which Activin A works as an antiviral. Further planned study includes the impact of Activin A which works as a better stimulator of innate response genes and significantly impacts upon HBV virions in cell culture. siRNA mediated inhibition of specific genes and/or CRISPR technology will be used to see if it affects the antiviral activity in the HepaRG cell line or other cell lines like the newly described Huh7 cells stably transfected with hNTCP (which we have established in the lab recently) is now known to act as a receptor for HBV and HDV. Activin A shows promise as an effective antiviral against HBV infection in the cell culture model. As it triggers potent host cell antiviral pathways, there is great potential to take this further into potential therapy. However, more work is needed to identify the mechanism involved in this process and its specificity before such trials can be planned. |
| Start Year | 2013 |
| Description | Professor Quentin Sattentau: Immune refocusing for influenza vaccine development |
| Organisation | University of Oxford |
| Department | Sir William Dunn School of Pathology |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | The aim of this project was design a universal influenza vaccine antigen that elicits antibodies that neutralize a broad spectrum of influenza A strains using novel 'glycan-masking' technology. This technology relies upon post-translational linking of immune-masking semi-synthetic glycans to specific residues (in this case lysines) on the protein surface, allowing site-directed silencing of variable antibody epitopes and re-targeting of the antibody response to conserved neutralization epitopes. |
| Collaborator Contribution | . |
| Impact | The project has (1) produced medium-scale quantities of soluble recombinant influenza HA, both wild-type and lysine modified, (2) verified that this glycoprotein is correctly folded and binds neutralizing antibodies directed to HA1 and HA2, (3) quantitatively adducted the SiaLac immune masking agent to the HA and achieved ~100% lysine occupancy and (4) immunized mice and demonstrated similar immunogenicity of both wild type and SiaLac-modified antigens. The immune silencing agent, SiaLac, was found to be immunogenic, and diverted a major proportion of the antibody response to SiaLac. This prevented the goal of shifting immune dominance towards conserved neutralization epitopes on the protein surface from being achieved. Since the project was highly successful with the exception of the unexpected immunogenicity of the SiaLac glycans, we intend to repeat the epitope masking using other immune silencing agents. At present we are investigating other types of sugar (polymerised sialic acid, mannose groups) and polymer (polyethylene glycol) for their silencing properties and will then link these to the lysine groups on the modified HA. |
| Start Year | 2013 |
| Description | Professor Sten Eirik Jacobsen: Therapeutic cycling and targeting of myelodysplastic syndrome stem cells |
| Organisation | University of Oxford |
| Department | Radcliffe Department of Medicine |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | This project had two objectives: (1) to study the impact of thrombopoietin mimetics on the cycling of normal HSCs and (2) to investigate the effects of thrombopoietin mimetics on MDS stem cells. Using state of the art in-vitro stem cell assays, we have established that Romiplostim cycles phenotypic human stem cells and enables enhanced elimination post chemotherapy. We are now performing experiments to establish the impact of Romiplostim to cycle and enhance elimination of functional stem cells. This should be completed by the end of the year. |
| Collaborator Contribution | Impact of THPO mimetics on the cycling of normal HSCs |
| Impact | We have an on-going collaboration with Dr Paal Holm, clinical lead in ITP at Rikshospitalet, University of Oslo, Norway, to study bone marrow samples from patients with ITP treated with Romiplostim. |
| Start Year | 2013 |
| Description | Professor Stephen G. Davies |
| Organisation | University of Oxford |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Models and assays for cancer/MDS stem cell targeting |
| Collaborator Contribution | chemical libraries for targeting of MDS stem cells |
| Impact | -Estabishment of spin-off company OxStem Oncology |
| Start Year | 2014 |
| Description | Rickard Sandberg |
| Organisation | Lund University |
| Country | Sweden |
| Sector | Academic/University |
| PI Contribution | Single cell studies of hematopoiesis and stem cells |
| Collaborator Contribution | Single cell rna sequencing expertise and analysis |
| Impact | As seen in publication output list multiple joint high impact publications |
| Start Year | 2006 |
| Description | Roche |
| Organisation | F. Hoffmann-La Roche AG |
| Country | Global |
| Sector | Private |
| PI Contribution | Hosting visitor to study membrane proteins and ligand binding using unique approaches developed in our laboratory |
| Collaborator Contribution | Contacts in industry |
| Impact | Invitation to visit F. Hoffmann-La Roche to give lecture and set up possible studentship. |
| Start Year | 2014 |
| Description | Sten Linnarsson |
| Organisation | Karolinska Institute |
| Country | Sweden |
| Sector | Academic/University |
| PI Contribution | Single cell analysis of stem and progenitor cells. |
| Collaborator Contribution | Sten Linnarsson is a world leader in single cell RNA sequencing and his input has been key to several of our reported publications utilising small cell number or single cell RNA sequencing (including Cell Stem Cell 2013; Cancer Cell 2014). |
| Impact | Publications as listed above. |
| Start Year | 2011 |
| Description | Thomas Milne |
| Organisation | University of Oxford |
| Department | Weatherall Institute of Molecular Medicine (WIMM) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Studies of mouse models of malignant hematopoiesis. |
| Collaborator Contribution | Expertise on molecular dysregulation in hematological malignancies. |
| Impact | See publication output, joint publication in Cancer Cell in 2018. |
| Start Year | 2010 |
| Title | ???????? |
| Description | ???????????????????45??????????????????????????????? |
| IP Reference | JPWO2017047707 |
| Protection | Patent application published |
| Year Protection Granted | 2018 |
| Licensed | Commercial In Confidence |
| Impact | Development of exon skipping therapy for Duchenne muscular dystrophy in collaboration with the Nippon Shinyaku Co, National Center Of Neurology And Psychiatry, Japan |
| Title | ANTI-VIRAL THERAPY |
| Description | This invention relates to a method of treating viral infections,and compounds for use in the treatment of viral infections by modulating the BMP/SMAD signalling pathway. In particular, it relates to methods and compounds for treating hepatitis C virus infection and/or influenza virus infection. It also relates to methods for identifying compounds that are useful in the treatment of viral infections, in particular hepatitis C virus infection and/or influenza virus infection. |
| IP Reference | WO2013005042 |
| Protection | Patent application published |
| Year Protection Granted | 2013 |
| Licensed | Commercial In Confidence |
| Impact | Anti viral therapy development |
| Title | Antibiotics |
| Description | The data from this work will provide additional supporting data for two patent currently in prosecution: "Antimicrobial compounds", Y.-C. Jeong and M. G. Moloney, UK Patent Application No 1211203.3; Isis Innovation Limited, PCT application (2012). "Antimicrobial compounds", Y.-C. Jeong and M. G. Moloney, UK Patent Application No 1211202.5; Isis Innovation Limited, PCT application (2012). |
| IP Reference | GB1211203.3 |
| Protection | Patent granted |
| Year Protection Granted | 2015 |
| Licensed | No |
| Impact | Possible spin out activity |
| Title | CHEMICAL COMPOUNDS |
| Description | A compound which is a pyridine or isoquinoline derivative of formula (I), or a pharmaceutically acceptable salt thereof, which is useful in the inhibition of ?- butyrobetaine hydroxylase (BBOX). The compounds are particularly useful in treatment of cardiovascular disease and diabetes. (I) |
| IP Reference | WO2015092412 |
| Protection | Patent granted |
| Year Protection Granted | 2015 |
| Licensed | No |
| Impact | N/A |
| Title | COMBINED THERAPEUTIC USE OF ANTIBODIES AND ENDOGLYCOSIDASES |
| Description | The invention relates to compositions comprising therapeutic antibodies, and uses and methods for increasing the potency of therapeutic antibodies. In particular, the invention provides a composition comprising (i) an agent which reduces Fc receptor binding of endogenous serum antibodies, and (ii) a therapeutic antibody, preferably a therapeutic antibody which is resistant to the agent. The therapeutic antibody may be administered to the subject after a set time interval, or the blood of the subject may be treated with the agent prior to administration of the therapeutic antibody. |
| IP Reference | WO2013110946 |
| Protection | Patent application published |
| Year Protection Granted | 2013 |
| Licensed | Yes |
| Impact | The IP was assigned from ISIS Innovation to a new spin-out company Immago Biosystems Ltd. Immago has subsequently entered into a development agreement with a European pharmaceutical company. |
| Title | Method and apparatus for quantifying lung function |
| Description | A method and apparatus for non-invasive assessment of lung inhomogeneity by accurate high temporal resolution measurement of respiratory gas flows at the mouth during steady state breathing and inert gas wash-in or wash-out and using these measurements to fit a mathematical model of the inhomogeneous lung. The model of the lung is based on modelling the lung as plural alveolar compartments each having an identical volume at functional residual capacity, but varying in its fractional share of total lung compliance, total pulmonary vascular conductance and total anatomical deadspace. A bivariate log-normal distribution of the lung compliance and pulmonary vascular conductance is used, together with a normal distribution of deadspace fraction. The model is fitted to the measurements using non-linear regression and the distribution of ventilation: perfusion ratios, lung compliance: volume ratios, lung vascular conductance: volume ratios and lung deadspace: volume ratios obtained from the fitted model are indicative of the airway condition and thus lung function of the subject. |
| IP Reference | US 16/328,773 |
| Protection | Patent granted |
| Year Protection Granted | 2019 |
| Licensed | No |
| Impact | A method and apparatus for non-invasive assessment of lung inhomogeneity by accurate high temporal resolution measurement of respiratory gas flows at the mouth during steady state breathing and inert gas wash-in or wash-out and using these measurements to fit a mathematical model of the inhomogeneous lung. The model of the lung is based on modelling the lung as plural alveolar compartments each having an identical volume at functional residual capacity, but varying in its fractional share of total lung compliance, total pulmonary vascular conductance and total anatomical deadspace. A bivariate log-normal distribution of the lung compliance and pulmonary vascular conductance is used, together with a normal distribution of deadspace fraction. The model is fitted to the measurements using non-linear regression and the distribution of ventilation: perfusion ratios, lung compliance: volume ratios, lung vascular conductance: volume ratios and lung deadspace: volume ratios obtained from the fitted model are indicative of the airway condition and thus lung function of the subject. |
| Title | Method of detecting the presence or absence of autoantibodies |
| Description | We developed a method, based on immobilised exosomes, for diagnostic testing of autoantibodies against a broad range of cell surface proteins. |
| IP Reference | US20160139119 |
| Protection | Patent application published |
| Year Protection Granted | |
| Licensed | No |
| Impact | None yet, but this is still work in progress. |
| Title | Scaffold |
| Description | A scaffold for tissue repair or wound dressing comprising: a material layer; a polymer fibre layer; and an adhesive component between the material layer and the polymer fibre layer, wherein the adhesive component comprises material having a lower melting temperature (Tm) than the material layer and the polymer fibre layer. |
| IP Reference | US10500310 B2 |
| Protection | Patent granted |
| Year Protection Granted | 2019 |
| Licensed | No |
| Impact | N/A as yet |
| Title | HDACi + Vaccination for HIV cure |
| Description | New use of combination therapy of HDAC inhibitors plus vaccination in primary HIV infection as a strategy to cure HIV. Funded by £1.7 million MRC DCS award. |
| Type | Therapeutic Intervention - Drug |
| Current Stage Of Development | Early clinical assessment |
| Year Development Stage Completed | 2013 |
| Development Status | Under active development/distribution |
| Impact | This combination of therapies is to be trialled in a clinical trial, with recruitment commencing in 2014 |
| Company Name | Oxford Antibiotics |
| Description | Antibacterial drug discovery |
| Year Established | 2017 |
| Impact | None at this stage (too early), but in active discussion with industry and investors to map future directions |
| Company Name | OxStem Oncology |
| Description | Co-founder of OxStem Oncology Ltd, Shareholder at spin-off company from Oxford University, UK. |
| Year Established | 2016 |
| Impact | Development of therapeutic targeting of cancer stem cells. |
| Company Name | Immago Biosystems Ltd (now acquired by Hansa Biopharma) |
| Description | Immago is developing innovations in the field of therapeutic antibodies arising from work in the Glycobiology Institute of the University of Oxford. With our technology we seek to enable a new generation of cancer therapies by enhancing the efficacy of therapeutic monoclonal antibodies (mAbs). Working with partners, we aim to develop better anti-cancer therapies, by improving the efficacy of existing and abandoned mAbs, and developing novel mAbs taking advantage of our unique knowledge of the field of therapeutic glycoproteins. |
| Year Established | 2013 |
| Impact | Immago Biosystems was acquired by Hansa Medical (now Hansa Biopharma). The technology is now branded as Enzyme-based antibody Enhancement and is described on their website as below. https://hansabiopharma.com/innovation-focus/our-technology/ Enzyme-based antibody Enhancement EnzE (Enzyme-based antibody Enhancement) is a pre-clinical research and development program under which the combined use of approved antibody-based cancer treatments with IgG-modulating enzymes is explored. High levels of plasma IgG have been associated with limiting the efficacy of therapeutic antibodies, as plasma IgG can saturate the Fc-receptors of the patient's immune cells and thereby prevent them from effectively killing the cancer cells. |
| Website | https://hansabiopharma.com |
| Company Name | OMASS THERAPEUTICS LIMITED |
| Description | OMass is an Oxford University spin-out company applying MS technology to drug discovery. The technology enables detection of drug leads that not only bind to the target complex, but also exert a functional effect through modulation of complex formation, with both effects, binding and function, being measured by a change in mass. |
| Year Established | 2016 |
| Impact | The methods developed by OMass are being applied to drug discovery for a variety of complex targets, including membrane receptors. |
| Website | https://omass.com/ |
| Company Name | PepGen |
| Description | PepGen, a new Oxford University Innovation spin out company. |
| Year Established | 2018 |
| Impact | Co-development with a pharmaceutical company in order to develop a novel multi-exon skipping approach with high efficiency for all DMD patients. |
| Company Name | VACCITECH LIMITED |
| Description | Vaccitech is a clinical stage T cell immunotherapy company developing products to treat and prevent infectious disease and cancer |
| Year Established | 2016 |
| Impact | Vaccitech is a clinical stage company utilizing a world leading T cell-inducing platform. The Vaccitech platform involves delivering either one or two heterologous viral vectors, each encoding the same antigen, several weeks to months apart for the most effective T cell induction |
| Website | https://www.vaccitech.co.uk/ |
| Description | 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 | Article in MRC Network Magazine - results not known Impacts not known - article |
| Year(s) Of Engagement Activity | 2014 |
| URL | http://www.mrc.ac.uk/news-events/publications/network-autumn-2014 |
| Description | Cheltenham Science Festival |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | Stand for NDM on HIV Cure at Cheltenham Science Festival |
| Year(s) Of Engagement Activity | 2015 |
| URL | http://www.cherub.uk.net |
| Description | Exhibit at Science Museum, London |
| 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 | Display at Science Museum in London on CHERUB, its research outputs and prospects for an HIV Cure |
| Year(s) Of Engagement Activity | 2015 |
| URL | http://www.cherub.uk.net |
| Description | Oxford NIHR BRC Open Day |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Type Of Presentation | Poster Presentation |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | Schools and members of the public visited the stall over the course of the day - at least 100 visitors - to learn about HIV, its treatment and drug resistance. Broad engagement across schools and general public. |
| Year(s) Of Engagement Activity | 2013 |
| Description | Public Lecture |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | Yes |
| Geographic Reach | Regional |
| Primary Audience | Schools |
| Results and Impact | Lecture initiated questions on working in STEM subjects Considerable interest from talented students to pursue career in research, particularly Oxford |
| Year(s) Of Engagement Activity | 2014 |