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Could a Lipid be the Key to Treating Chronic Inflammatory Diseases?

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Article

Could a Lipid be the Key to Treating Chronic Inflammatory Diseases?

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Not too long ago, we received some exciting news surrounding the potential clinical benefit of a lipid possessing potent anti-inflammatory properties. This lipid, 10-nitro-oleic-acid, an endogenous nitro-fatty acid (NFA) modulator, was initially discovered by researchers based at University of Alabama, Birmingham (Bruce Freeman and colleagues). Subsequent to this, its anti-inflammatory actions were reported by  Cardiff University, UK, in collaboration with colleagues from the universities of Michigan, Oregon and Pittsburgh, USA.

In depth research conducted by both Prof. Valerie O'Donnell, Co-Director of the Systems Immunity Research Institute, University of Cardiff and Prof. Bruce A. Freeman, Department of Pharmacology and Chemical Biology, University of Pittsburgh originally identified the lipid’s ability to reduce inflammation in circulating hematocytes. Prof O’Donnell provided comment for a press release issued 1st September 2017: “The discovery that this lipid has potent anti-inflammatory activity is now being used to develop therapies that could significantly improve the lives of people with life-threatening diseases.” 1

Complexa, a biopharmaceutical company aimed at advancing novel treatments using endogenous cell signalling technologies, now plans to conduct Phase II trials using 10-nitro-oleic-acid in patients with focal segmental glomerulosclerosis (FSGS) and pulmonary arterial hypertension (PAH).1,2 10-nitro-oleic-acid appears in Complexa’s investigational product pipeline as CXA-10. The Phase II studies follow on from a number of completed trials investigating the safety, tolerability and pharmacokinetics of CXA-10.2

CXA-10 inhibits the inflammatory molecule nuclear factor (NF)-κB and upregulates the inflammatory molecule Nrf2.3 It also drives the expression of heat shock proteins and inhibition of xanthine oxidoreductase, impacting cellular and oxidative stress, respectively.

In light of this recent announcement, I contacted Professor Valerie O’Donnell to learn more about her expertise and interest in the topic, her group’s research and her opinion on the potential implications of this development.

LM: Could you tell me a little more about your scientific background. Was there something that particularly inspired your focus on understanding the role of novel lipids in vascular inflammation?

My research concerns the biochemistry of lipids, particularly understanding how these small molecules and their oxidative metabolism regulates vascular biology and inflammation. I first started working on lipid oxidation during post-doctoral fellowships at the University of Bern, Switzerland and University of Alabama at Birmingham. The work I conducted in the USA particularly inspired me to continue to research the role of lipids in inflammation throughout my career. It was a transformational time for me working in Bruce Freeman’s laboratory in the late 1990’s, the work being undertaken in the group was inspiring. I realised how much there still was to discover about how lipids regulate vascular health and disease. Even now I feel we are only at the tip of the iceberg, there is still an awful lot we do not know about how this important class of molecules control essential processes of innate immunity, including regulating blood clotting, bacterial invasion, wound healing, etc.

LM: A media release issued on the 1st September 2017, mentioned your group’s involvement in the initial discovery of the anti-inflammatory properties associated with the lipid 10-nitro-oleic-acid, could you provide more information about this lipid and the associated research?

When I joined Bruce’s lab in 1996, nitrolipids had only just been discovered.  Vascular biology research at that time was especially focused on the recent discovery that the gas nitric oxide was made by blood vessels and used to control blood pressure (a finding by Louis J.  Ignarro and others that led to the Nobel Prize for Physiology and Medicine in 1998).


Robert F. Furchgott, Louis J. Ignarro, and Ferid Murad receiving he Nobel Prize in Physiology or Medicine 1998

The idea Bruce and his colleagues had was that the convergence of oxidation and nitration mediated by by-products of nitric oxide would lead to the formation of new biological compounds that could be biomarkers or mediators of vascular inflammation. Bruce’s lab in particular was interested in nitrolipids and their formation in atherosclerosis and inflammation.

My project focused on trying to understand the chemical mechanisms by which these lipids form, since both nitration and oxidation of lipids is complex and unpredictable and can lead to a myriad of different biomolecules all with unique biological characteristics. My challenge was to determine which of these could form in cells, and how, and then use this information to generate new nitrolipids that could be followed up as potential biomediators of vascular disease. By the time I came to Cardiff in 1999 on a Wellcome Trust fellowship, I had become interested in how nitrolipids regulate the activity of circulating vascular immune cells and platelets. These cells are critical for wound healing, preventing bleeding and infection, and mediating repair.

In the first few years in Cardiff, my group working with Bruce and colleagues, published two studies showing that the lipids could decrease both platelet and neutrophil activation in response to either thrombin or bacterial stimuli. These papers were the first proof-of-concept that nitrolipids are anti-inflammatory. Following this, studies from Bruce’s lab showed that the lipids were reactive electrophiles, and could potently dampen down inflammation through two key mechanisms, namely inhibition of NF-κB and activation of Nrf2. These are both critical control transcription factors that act in concert to either upregulate or dampen inflammatory responses, respectively. Their involvement in many acute and chronic conditions is well established. To date there are few drugs that effectively target these proteins, making them a highly attractive pathway for therapy development. We were pleased that these discoveries led to a core patent protecting nitrolipids and their therapeutic applications. This intellectual property, on which I am a co-inventor, has been licensed from the Cardiff University by Complexa.

LM: Following on from the above question, in your opinion, what potential clinical benefits could result?

Given the involvement of these transcription factors in virtually all chronic and acute inflammatory conditions, the potential clinical benefits are huge. 

A Phase II clinical trial using CXA-10 in patients with FSGS, is expected to start in early 2018. This rare disease leads to scarring in the kidney, reducing kidney function and causes up to 70% of patients to develop end-stage renal failure. Once dialysis is needed, average life expectancy is only eight years. There are no approved therapies for FSGS, and patients often have to take high-dose steroids for long time. CXA-10 is being investigated as a steroid-sparing agent in recently diagnosed patients.

A second Phase II trial of oral CXA-10 as a disease-modifying treatment for PAH will also start very soon. This disease leads to exercise intolerance, breathlessness, heart failure and death, with average survival of only 5–7 years. Current treatments are limited to vasodilators that do little to improve outcome. CXA-10 has shown disease-modifying activity in preclinical models of PAH, and will be tested along with existing standard of care.

Beyond this, if these trials are successful, CXA-10 could be advanced as a treatment for many acute and chronic metabolic and inflammatory diseases where modulating NF-kB and NRF-2 signaling would be beneficial.

LM: Will your group be continuing research in this area? If so what direction will this take?

Beyond our two papers from Cardiff, studies on the anti-inflammatory actions of these unique lipids were led by Bruce’s group, initially at University of Alabama at Birmingham, and then when he moved to University of Pittsburgh in the mid 2000’s. 

During that time, research from Bruce and his colleagues’ laboratories found that CXA-10 increases the expression of heat shock proteins, which act as protective agents during cellular stress, and block an enzyme called xanthine oxidoreductase, leading to reduced oxidative stress. It was also found that CXA-10 demonstrated proof of target engagement in five Phase I human safety studies, and has demonstrated safety in over 100 subjects. Importantly, CXA-10 has demonstrated activation of target gene expression and subsequent inhibition of key biomarkers of disease-related inflammation and fibrosis. With Dr Margaret Tarpey, Bruce established a spin-out company, Complexa, to which CXA-10 is now licensed and being developed for multiple anti-inflammatory indications aforementioned. Complexa recently raised $62M in Series C funding for Phase II clinical trials.

Our own research in Cardiff is now mainly concerned with enzymatically-oxidized phospholipids (eoxPL), in particular families of these lipids that are generated by immune cells and platelets to regulate innate immune responses and coagulation. By their nature these lipids contain fatty acids, although their biochemical characteristics are very different to free acid analogs such as nitrolipids.  With Bruce and his group, we have started to consider how nitrolipids, attached to larger functional groups such as phospholipids, might have unique bioactivities themselves, however this is at a very early stage.

Prof. O’Donnell’s team have developed a Python workflow for novel lipid discovery, more information can be found here.

References

1. Turning lipids research into new drugs - News - cardiff.ac.uk. (2017, September 1). Retrieved September 8, 2017, from: http://www.cardiff.ac.uk/news/view/910011-turning-lipids-research-into-new-drugs

2. Complexa announces Successful Completion of Four Phase 1 Studies of CXA-10 and Planned Phase 2 Initiation in Multiple Orphan Indications during 2016. (2015, November 12). Retrieved September 08, 2017, from: http://www.complexarx.com/complexa-announces-successful-completion-of-four-phase-1-studies-of-cxa-10-and-planned-phase-2-initiation-in-multiple-orphan-indications-during-2016/

3. Product Pipeline. (2014). Retrieved September 08, 2017, from: http://www.complexarx.com/product-pipeline/


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Laura Elizabeth Lansdowne
Laura Elizabeth Lansdowne
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