Rheumatoid arthritis

Dr Cynthia Louis: exploring the role of TBK1 inhibition in inflammatory arthritis

Tuesday, 31 Jul 2018

Describe the aim of this project.

I am studying multiple biological sequela of autoimmune arthritis, aiming to form a multipronged approach in treating arthritis and other autoimmune diseases by silencing autoimmunity and inflammation.

What have you discovered so far about the potential of TBK1 inhibition?

I have discovered that there are many facets to TANK-binding kinase 1 (TBK1) immune regulation. Although TBK1 was once thought to be mainly driving type 1 interferon responses strongly associated in lupus pathogenesis, other studies and our results suggest the therapeutic potential of targeting TBK1 in a germinal center-driven, autoantibody-mediated arthritis model. In short, TBK1 inhibition may target upstream autoimmune events. These findings may pave way into investigating TBK1 involvement and inhibition in other germinal center-driven autoimmune conditions.

What aspect of this particular research excites you the most?

The most exciting aspect of this research is the translational potential into the clinics, with prospective relevance ranging from rheumatoid arthritis but also other autoantibody-driven diseases such as lupus, Sjogren’s syndrome, myasthenia gravis and vasculitis. Further studies are required to test TBK1 as well as germinal center involvement in these discrete diseases. TBK1 functions also appear to be much broader beyond type 1 interferon response and germinal center reaction, which prompt my ongoing effort into elucidating TBK1-regulated biological processes in discrete immune cells and how these findings may be harnessed towards characterisation of novel therapeutic targets in autoimmunity.

What’s important to know about germinal centers in inflammatory diseases?

It is important to recognise germinal center (GC) as one of key components in the development of autoantibody-mediated diseases. This specialised structure often develops in lymphoid tissues during early pre-symptomatic stages of disease that promotes interactions of autoreactive immune cells, the production of disease-inducing autoantibodies, and followed by symptomatic inflammatory arthritis. Indeed, overactive GCs have been associated with sustained autoantibody production and autoimmune inflammation in some cases. By understanding regulators of productive pathogenic GCs, we can then rationally target GCs as a mode for silencing autoimmunity, among other forms of autoimmune reactions.

This looks like early research. How long before it might impact patient care?

We aim to translate our research in the next three years. Paralleling our research into novel functions of TBK1 in cell physiology, we are also planning to test TBK1 inhibition in other models of autoimmune diseases, paying particular attention to discrete pathogenic immune pathways.

What’s your Holy Grail – the one thing you’d like to achieve in your research career?

I would like to understand more about the pathogenesis of other complex autoimmune conditions, not just RA. By identifying overlapping and/or discrete pathogenic immune pathways as part of diagnosis, the development of new therapies, targeted treatment, and repurposing of currently available ones may improve current treatment. This is particularly relevant for other autoimmune conditions with less therapeutic options than RA.

What is your biggest research hurdle?

Target specificity of the inhibitor is one. At the moment, it also targets other closely related kinases. We are looking forward towards development of pharmacologically suitable compound for future clinical trials, whereby optimising safety and pharmacokinetic profile is key towards translation. Paralleling future development, rigorous preclinical therapeutic testing and immunological studies would be instrumental in gauging and minimising potential side effects.

A second hurdle is funding. Because autoimmune diseases encompass a wide spectrum of immune dysregulations, there will always be a window of opportunity for novel therapies in patient care. Continuous funding into immunological research, preclinical and clinical trials into novel therapeutic targets is imperative to support progress, especially research into other autoimmune diseases with less therapeutic options.

Who has inspired you in work or life?

Success stories from basic science to clinical applications, driven by many hard working researchers, always inspire optimism towards my research. I am yet to find specific inspirational figures since I am still quite early in my career trajectory.

Describe your perfect day.

A perfect day would be when all experiments work according to plan, results fitting original hypothesis, and having the time to exercise after work. More recently, I also find that unexpected results (albeit challenging and disappointing at times) with more time and research effort can give similar effect by coming up with new ideas and plans. Receiving positive outcomes on submitted manuscripts or funding applications is also a plus.

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