Our technology can be applied across all inflammatory diseases, both chronic and acute
Initial product focus is on: Rheumatoid Arthritis, Cardiovascular Disease, Sepsis & Trauma where substantial unmet clinical need exists.
We have identified a portfolio comprising several unique LMS biomarkers, one of which is partnered and a novel therapeutic opportunity. Our plan is to develop our product pipeline opportunities in parallel.
We envision that signature diagnostic profiles, identified using our proprietary LMS discovery platform, will be delivered using scalable diagnostic technology formats that will include immunoassays and biochip technologies.
Human Diseases where lipid mediators are dysregulated
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Diagnostic and therapeutic potential of lipid mediators
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Cardiovascular diseases, including atherosclerosis, are one of the leading causes of mortality in the 21st century. It is now apparent that in addition to elevated circulating cholesterol, several factors are also responsible for the onset and propagation of cardiovascular diseases, with the inflammatory status of the vasculature being regarded as a key element in both arms of this pathological process.
Proof of concept
Studies from the Founder’s laboratory found that the ability of distinct statins to regulate inflammation in experimental systems was linked with their ability to regulate a select group of protective mediators. Notably inhibition of these molecules reversed the immunomodulatory actions of statins. Furthermore, assessment of plasma concentrations of these mediators in a small cohort of patients that received statins demonstrated a link between increased circulating concentrations of these molecules and a reduction in the risk of cardiovascular events. These findings supporting the potential prognostic utility of measuring plasma concentrations of these molecules in predicting the effectiveness of statin therapy in regulating cardiovascular inflammation.
Therapeutics that Resolomics will focus upon for development of novel LMS include:
- PCSK9 inhibitors
- anti-Interleukin 1 biologicals
These drugs, and in particular their vascular indications, are relatively new, consequently, the target populations where they may have best effect are not yet well defined. Since both therapeutic strategies directly (anti-IL1/IL1-RA), or indirectly (PCSK9), target pathways within the inflammatory response, we anticipate that their ability to impact inflammation, and therefore lipid mediator production, will reflect their ability to regulate disease progression.
Whilst most available therapeutics are effective in ~50 % of patients, there are to date no prognostic biomarkers that can accurately predict whether a patient is likely to respond to a given treatment or not. The front-line drugs in the treatment and management of patients with rheumatoid arthritis (RA) are non-biological disease modifying anti-rheumatic drugs (DMARDs).
Proof of concept
We demonstrated that plasma concentrations of a small group of lipid mediators were predictive of patient responsiveness to DMARDs with an accuracy >85%. Peripheral blood concentrations of these mediators were diagnostic of different disease synovial pathotypes (myeloid, lymphoid, fibrotic) suggesting a utility for patient stratification and therapy assignment.
A second group of therapeutics, widely used in patients with RA, are biologics; these are usually antibodies to specific molecules or receptors involved in disease propagation. For example, cytokine Tumour Necrosis Factor alpha, has been implicated in disease progression in RA and yet blocking this cytokine results in effective disease reduction in approximately 50% of patients. We are currently applying LMScan™ technology to predict treatment outcome in collaboration with a European diagnostic company. The aim is to identify LMS that can be used as diagnostics for predicting patient responsiveness to therapy. Our diagnostics partner intends to transfer a commercially viable biomarker onto a scalable platform for use as a point-of-care diagnostic.
Cardiovascular comorbidities are responsible for around half of all deaths in patients with RA. Unexplained risk factors of congestive heart failure in RA patients are likely related to systemic and local inflammation, but these mechanism remains incompletely understood. No marked beneficial cardio-protective effects have been observed for any class of the current RA medications. Therefore, identification of patient subgroups at risk of developing heart failure could determine the assignment of an optimum anti-rheumatic drug and encourage early intervention of therapies for preventing loss of cardiac function.
Resolomics will undertake LMS development in relation to:
- Response to specific small molecular therapeutics (e.g. JAK inhibitors, DMARDs)
- Response to specific biologics
- Identify a LMS to predict patients at risk of developing heart failure.
Therapeutic opportunities in rheumatoid arthritis
In pre-clinical studies performed in the Founders’ laboratory a cell therapy-based approach has been developed, whereby cells are isolated from animals with arthritis, reprogrammed in vitro and re-injected back into diseased mice. Notably, in addition to reducing joint disease activity, application of the reprogrammed cells promoted repair and regeneration of damaged tissues. Resolomics will develop this procedure to establish its clinical efficacy as a co-therapy with current standard of care. Resolomics will develop LMS companion diagnostics in parallel to evaluate treatment efficacy and identify those patient populations that are most likely to benefit from these approaches.
Sepsis & Trauma
Sepsis is one of the leading causes of morbidity and mortality. It is estimated to affect 30 million people worldwide each year, potentially leading to 6 million deaths per year. When patients are hospitalized at present it is not possible to predict disease course, an aspect that has severely hindered the treatment approaches that are available to physicians. Most patients are treated based on the symptoms they present. Patient management is further confounded by the fact that in many cases patients are hospitalised at different stages during the disease course, therefore clinicians may not know when the infection started.
Proof of concept
Pre-clinical studies, including those from the Founders’ laboratories, have shown that alterations in the production and/or actions of lipid mediators, in particular those of specialized pro-resolving mediators, are linked to dysregulated inflammation and poor outcomes. Congruently, administration of these molecules to experimental models of infection, both bacterial and viral, is linked to improved survival in experimental sepsis models, often associated with a reprograming of innate immune cells. Studies in humans support a role for these molecules in regulating host responses to infection: in a human experimental model of dermal infections, administration of specialized pro-resolving mediators accelerated termination of inflammation as well as clearance of specific white blood cells from the site of infection.
The Founders assessed the prognostic value of peripheral blood lipid mediator concentrations in establishing disease outcome. Plasma lipid mediator concentrations of selected mediators were different upon admittance to the intensive care unit in those patients that did not survive when compared with those that did. Lipid mediators were also linked with the onset of pulmonary complications, inferring that in immune-compromised patients, levels of these molecules may predict disease course.
Resolomics will identify diagnostic LMS markers commencing with specific patient cohorts, namely:
- patients with community acquired pneumonia
- patients with bacterial peritonitis
- patients with infections following myocardial infarct
- post-traumatic patients with or without infections
- COVID-19 infections
Our technology can be applied across all inflammatory diseases
Enhanced diagnostic signatures for patient stratification and improved clinical management of human diseases
William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square
LONDON EC1M 6BQ