Translating the Resolution of Inflammation: MC3 in human arthritis synovia

Overactive cells within the arthritic joint can be detrimental and destructive leading to the painful and debilitating disease called Rheumatoid Arthritis (RA; affecting ~1% of western world population). For the last twenty years we have studied the nature and impact of biological pathways existing within our bodies to resolve the hyperactivity of these inflamed cells and thus improve disease outcome. One such pathway is the focus of the present project.

We have so far applied molecular (observing genes) and pharmacological (using natural and synthetic molecules/compounds) approaches, to understand how this biological system - which is naturally expressed in our body - can control and resolve inflammation: WE NOW NEED TO TRANSLATE OUR FINDINGS TO HUMAN DISEASED CELLS, and indeed are ready!

Our preliminary data indicates that treatment of inflamed tissue and cells from the RA joints with synthetic compounds (mimicking the natural proteins of this biological pathway) decreases the generation of 'bad' molecules that cause joint destruction. These molecules (e.g. TNF) being 'bad' in the sense that they can perpetuate the disease by enhancing the activity of and recruiting white blood cells to the joint, as well as dampening the response of the 'good' cells.

Thus we ask two main questions:

1) Is the novel biological pathway active in RA joints? And how does it operate.
2) Can we harness the biological pathway (and specific proteins within the pathway) with currently available synthetic hormones/molecules, to reduce hyperactivity within the RA joint, with particular focus on specific and detrimental cells within the joint?

We will take joint tissue (from patients undergoing knee/hip replacement therapy or from ultrasound-guided biopsies) and culture this in an environment which would mimic the natural conditions. Therefore, in these cultures i) we will test our synthetic compounds to validate the biological pathway operative in the RA joint to confirm this line of research is feasible for development of potential new therapeutics for RA; ii) we will extract cells from RA joint to dissect the anti-inflammatory actions evoked by our synthetic therapeutics. We will study the production of molecules that these destructive cells produce.

Finally, we will capitalize on a unique biobank of synovial tissue (collected thanks to MRC funding, via the Pathobiology of Early Arthritis Consortium [PEAC], led by one of the applicants) to study potential modulation of elements of this pathway (mediators/enzymes/targets) in relation to i) disease stage and ii) therapeutic management.

We are confident completion of the project and, potentially, affirmative answers to the main questions will pave the way to the development of new anti-arthritic therapeutics that will capitalise on the 'natural resolution of inflammation' concept. The novelty of our approach lies in the validity of exploiting targets fundamentally used by our body to naturally resolve inflammation, translating our work into the human settings to achieve clinical benefit for patients that have poor quality of life due to this debilitating disease. The results produced with this project will provide strong support to our current effort to engage academic/industrial collaborators to the design and development of therapies, expecting that these novel therapeutics will be burdened by a much lower degree of side-effects than those observed with current therapies.

Finally, it should be noted that new therapeutics depicting on this pathway are now emerging (tested in Phase IIb and licenced to big pharma), and that we are actively engaged with MRC Technology to exploit this line of research for novel and specific molecules. Therefore, this investigative and exploratory (essentially academic) project will inform parallel efforts in relation to drug discovery programmes.

We have investigated mechanisms of the host response for over 20 years, with a focus on mediators and pathways that are activated in our body to keep under check the inflammatory response mounted against xenobiotics and other injurious agents. Examples are dissection of the biology of corticosterone (the rodent equivalent to cortisol), Annexin A1 and - relevant here - melanocortins. Thus, there is a need for a better understanding of key regulatory elements both in relation to tissue response to injury and its development versus chronicity instead of resolution. Here we focus on a new potential effector of the resolution of inflammation, the melanocortin receptor type 3 (MC3).

Supported by recently published work (and a wealth of unpublished data) produced collectively by the Applicants, this project puts forward the hypothesis that MC3 is a novel, and possibly discriminatory, effector of resolution. Often 'shaded' by the ubiquitous MC1 receptor, MC3 can be upregulated in conditions of inflammatory stress to convey inhibitory signals, perhaps in a ligand-biased fashion. We postulate that peripheral generation of MC ligands could also occur in the RA synovia.

This research projects represents a step-change in current views of melanocortin biology, moving to a fully human experimentation. Supported by consistent preliminary data generated with human RA synovia (and fibroblasts), and supported by a linear rationale, we will assess:

Aim 1: The regulation of MC3 expression, and other elements of the melanocortin pathway, in human synovia, attempting to relate it to the disease status (early vs. late arthritis; resolving vs. persistent arthritis) and therapeutic application (tissue analysis before and after treatment).

Aim 2: The pharmacology of MC3 agonists, using peptide-mimetics and small molecules, defining their effect on human tissue and cell activation, to unveil the potential for this research for the development of future therapeutic agents.

This proposal seeks to elucidate the role of MC3 in human synovia. Although this is a basic research project, the longer term findings of this research could have provide a better understanding of ENDOGENOUS CONTROL OF INFLAMMATION-MEDIATED DISEASES. It is becoming clear that inflammation is involved in a wide range of pathologies including atherosclerosis, Alzheimer's disease, cognitive impairment, colitis, arthritis and cancer, which have huge social and economic impacts, particularly in Western societies. Improved understanding of the mechanisms underlying these diseases could suggest potential new therapeutic approaches and new targets for therapeutic intervention. Hence, our research programme will potentially impact on a considerable number of other beneficiaries alongside the academic research community including the commercial private sector, charities, other public bodies and government department and of course the wider public.

INDUSTRY. The proposed research could benefit pharmaceutical, biotechnology and diagnostics companies in the commercial sector by suggesting potential new therapeutic approaches and targets. In particular, we think that there may be long-term prospects for novel and selective MC3 agonists. It is very recent the licensing of AP214 (a pan-MC receptor agonist) from Action Pharma AS to Abbott for $110M (http://www.actionpharma.com/) providing strong proof-of-concept that new therapeutics can indeed be generated from this line of research.
We will, therefore, assess our research findings for patentable outcomes or materials or processes that could be licenced. In addition, the academic knowledge and expertise gained through this research will provide high quality academic support for industry internationally. Specifically, we propose to attend the international conference BIO or Bio2Business events.

CHARITIES AND GOVERNMENT AGENCIES. The research outputs will be of interest to charities and government agencies seeking to support healthy ageing and improved treatments for chronic diseases. Representatives from charities and funding bodies often attend events at Barts and The London Medical School. As example, every year we hold the William Harvey Day a celebrative day of the School of Medicine that is attended by representatives from the Wellcome Trust, The British Heart Foundation and The Wolfson Foundation.

WIDER PUBLIC. In the longer term, the wider public may benefit from our research in that it may lead to an improved understanding of the inflammatory mechanisms involved in a wide range of diseases that have huge economic and social costs. The research outputs could potentially contribute to the development of new treatments for sufferers of these diseases. Also, they may inform preventative approaches that could improve quality of life and contribute to healthy ageing in the wider population.

TIMESCALES FOR THE BENEFITS TO BE REALISED. We are well-placed to commence the project swiftly with Dr Montero-Melendez already equipped with the practical, experimental and intellectual abilities to start working on it from day 1. In the academic research context, impact will be generated both during and immediately on completion of the project, through communication of the research in scientific publications, conferences and other dissemination activities. Longer-term impacts, for example the development of new therapeutics, could be realised over 10-20 years through follow-on funding and commercialisation activities.

TRANSFERABLE SKILLS THAT STAFF WORKING ON THE PROJECT WILL DEVELOP. In addition to working in a multidisciplinary and international research labs, the researcher working on this project will have the opportunity to develop project management and communication skills that could apply in many employment sectors. She will be exposed to issues/problems related to the use of clinical samples