Synthetic-interferon mimetics as potential cross-species therapeutics
Lead Research Organisation:
University of Edinburgh
Department Name: MRC Human Genetics Unit
Abstract
The interferons (IFNs) are a family of cytokines that protect against disease and viral infection and which can be exploited in immunotherapy strategies to treat a range of diseases across mammalian species. The consequences of introducing therapeutic IFN to patients are both a direct effect on the target cells and a more indirect response through activation of the immune system (Parker et al. 2016; Zitvogel et al., 2015). A major barrier to widespread use of naturally occurring IFN-molecules in both humans and companion animals, such as dogs, is their pleiotropic nature and severe side-effects when delivered at appropriate doses. The University of Edinburgh is working with Alfacyte whose mission is to develop innovative synthetic alpha-interferons with an improved side-effect profile as biologics to treat a variety of conditions. In Edinburgh, we aim to generate and characterise the mechanism of action of IFN-mimetics generated form bespoke synthetic combinatorial libraries that can be used to screen for biologics with desirable characteristics, such as stability and bioavailability. We are also seeking synthetic IFN derivatives which favour activation of one branch of the immune response over another. Using information gained from screening in combination with computational biology we aim to optimise potential IFN-pathway targeted biologics as new across-species agents. To understand the mechanism of action of IFN-mimetics the effect of potential biologics on cellular signalling and proteostasis will be investigated using a systems proteomic approach. This will involve a systematic analysis on the localisation, interactions, modification and function of key downstream IFN-activated signalling pathways/protein in appropriate primary cell, stem cell and immune cell models. This approach is designed to identify 'omics'-based biomarkers as a readout of the response to synthetic-IFN and determine the potential utility of next generation IFN-mimetics in the treatment of diseases such as cancer which would benefit from the One Health approach of comparative medicine to treat both humans and companion animals.
The student will work as part of team focused on using synthetic- and computational-biology to identify candidate biologics in the first part of their PhD. They will then carry-out systems proteomics and bioinformatics analysis in selected cell models in the second half of their studies before validating candidate biomarkers. In addition, the student will have access to expertise and training with Alfacyte. The student will therefore receive interdisciplinary training in biochemistry, synthetic biology and in silico protein modelling as well as systems based proteomic analysis linked to bioinformatics and industry standard immunological assay development.
The student will work as part of team focused on using synthetic- and computational-biology to identify candidate biologics in the first part of their PhD. They will then carry-out systems proteomics and bioinformatics analysis in selected cell models in the second half of their studies before validating candidate biomarkers. In addition, the student will have access to expertise and training with Alfacyte. The student will therefore receive interdisciplinary training in biochemistry, synthetic biology and in silico protein modelling as well as systems based proteomic analysis linked to bioinformatics and industry standard immunological assay development.
| Description | This work aimed to investigate the full diversity of the human IFN alpha gene family, to explore their potential as cancer therapies. During the work we have seen that the IFN alpha which is used in the clinic, IFNa2, may not be the most effective cancer therapy. We have seen that there are differences in the biological and physical properties of IFN alphas, which are relevant to the use of IFNs as cancer drugs. In particular, we have seen that tumours develop mutations to their IFN signalling mechanisms which play a part in cancer biology. Ongoing work understanding these mutations is needed to fully appreciate their role, however it seems that the IFN signalling axis has a key role in cancer immunotherapy, and in tumour evasion of the immune system. |
| Exploitation Route | The findings of the work so far provide a basis to trial a wider range of IFN alphas in a clinical setting, but there is also much more investigation into IFN biology still to be done. The lack of research into the diversity of IFN alphas needs to be addressed; and the structural and physical aspects of IFN biology which have been probed in this investigation provide a basis for that ongoing research. |
| Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
| Description | During public engagement events organised by CRUK I have discussed my work with a number of members of the public, as well as discussing cancer research as a wider field. In these conversations I feel that I have been able to communicate some of the general approaches to cancer research and developing therapeutics, as well as the importance of basic biology research to addressing therapeutic issues. Using specific examples of my own research, and research from the IGMM ECRC as a whole, I have been able to describe the realities of scientific research and in this way have hopefully increased people's understanding and appreciation for scientific research. |
| First Year Of Impact | 2018 |
| Description | Doitsidou lab collaboration |
| Organisation | University of Edinburgh |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Throughout this collaboration, I worked with Maria Doitsidou and her colleague Eugenia Goya on the publication of their paper 'Probiotic Bacillus subtilis Protects against a-Synuclein Aggregation in C. elegans'. This collaboration began as we in the Ball lab have worked on alpha-synuclein and Alzheimers, in the context of the protein Hsc70 C-terminal Interacting Protein (CHIP). As CHIP is a regulator of proteins in the IFN signalling axis, especially IRF1, this project crossed over with some of my work. We provided collaboration on some experiments, specifically including immunoblot analysis of C.elegans samples, as well as editing of the manuscript. |
| Collaborator Contribution | The majority of this paper was completed by Eugenia and Maria and members of the Doitsidou lab, my contribution was in some experimental help and editing of the manuscript. |
| Impact | This collaboration resulted in the publication of Eugenia's paper mentioned above, in Cell Reports earlier this year. Our lab is now establishing a longer-term collaboration with the Doitsidou lab, with one PhD student working between the two labs and using C.elegans as a model, which is new for the Ball group. There will also be another student starting in September, working between the two labs. This is generating multi-disciplinary work to the extent that the Ball lab hasn't previously used C.elegans in our research, and our lab is able to offer well established experimental routes to the Doitsidou lab, such as proteomics. |
| Start Year | 2019 |
| Description | Edinburgh Science Festival |
| Form Of Engagement Activity | Participation in an open day or visit at my research institution |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Public/other audiences |
| Results and Impact | As part of the Edinburgh Science Festival, CRUK organise public engagement activities based on the research performed at the IGMM ECRC, which is then staged at the National Museum of Scotland. In each year an activity was used to engage audiences with research methods and topics from the IGMM. As well as providing the activity, pamphlets are provided with more details about CRUK's work, and these sparked discussions with members of the public. The specific research areas addressed by the activity sparked wider questions from all audiences, and allowed informative discussions. A lot of people that came to the event had their own questions to ask, and this meant that many people went away with a greater understanding of cancer biology and research, which was often relevant to their own/family experiences of cancer. On one occasion, a clinician asked for information about researchers at the University, looking to set up collaborations. I provided him with contact details for relevant research groups. |
| Year(s) Of Engagement Activity | 2018,2019 |