A research team from the Ulster University Centre for Personalised Medicine has developed a novel therapy which could have far-reaching implications for patients suffering from glaucoma, cardiovascular disease, diabetes and a range of other conditions associated with chronic inflammation.
Led by Dr Vicky McGilligan, the team has developed a novel inhibitor to the NLRP3 inflammasome, a protein which has a role in mediating the body’s inflammatory response to injury or illness.
“Inflammation is part of the way the body protects itself, but it is also a primary contributing factor involved in multiple chronic diseases,” says Dr McGilligan. “Additionally, patients with a chronic inflammatory disease are at greater risk for developing other inflammatory related conditions. Chronic inflammation can cause considerable damage to the tissues of the body, and it can lead to a variety of problems, depending on where it is located.”
World first
She explains that the NLRP3 inflammasome protein is well known to be involved in orchestrating chronic inflammation in many degenerative and infectious diseases including cardiovascular disease, diabetes, neurological diseases such as Alzheimer’s, arthritic conditions, inflammatory eye conditions including AMD and glaucoma, and depression.
The Ulster team has developed the world’s first biological therapy to target NLRP3 and proof of concept tests have shown it exhibits superior anti-inflammatory activity. The therapy, known as Inflammab, has been shown to inhibit the activity of the NLRP3 inflammasome and dampen its effects.
Dr McGilligan has a long track record in this area of research. "I come from a wet lab background and I started out working on inflammatory bowel disease," she explains. "I went into industry and then did a postdoctoral research at University of Dundee. After that I moved to Harvard Medical School where I did a training fellowship under Meredith Gregory-Ksander and during that time became interested in NLRP3."
Gregory-Ksander is recognised as the first person to identify a protein in the conjunctiva which has an involvement in glaucoma. “It plays a critical role in protecting the body but when it gets out of control and hyperactive doesn’t switch off it leads to chronic inflammation. We know that it is implicated in a lot of different conditions and inflammatory diseases, even depression.”
On her return from Harvard she joined Belfast-based drug discovery and development firm Fusion Antibodies. “I learned a new skillset in antibody treatment development while I was there,” she notes. “When I left there for Ulster University, I had new skillset in therapeutic antibodies, and I came up with the idea of using them to inhibit inflammation.”
The first target disease area was glaucoma, the leading cause of irreversible blindness and a global problem that affects over 60 million people. There is no cure for this disease as yet, and numbers diagnosed with the condition continue to rise, partly as a result of the aging population. The only treatment at present involves intraocular pressure (IOP) reduction.
The disease is characterised by the progressive loss of retinal ganglion cells (RGCs). “We have demonstrated in mice that Inflammab can inhibit the death of RGCs,” says McGilligan.
Harmful
The NLRP3 inflammasome has been shown to become activated during glaucoma. Excessive or prolonged inflammation can lead to a harmful response that further damages the nerves in the eye. Regulating inflammation by targeting the NLRP3 inflammasome can help prevent vision loss in glaucoma patients.
People may not associate inflammation with coronary artery disease, but it is driven by chronic inflammation of the blood vessels supplying the heart. The resultant atherosclerosis can lead to blockages, heart failure and other acute events. The NLRP3 inflammasome has been found to have a central involvement in this inflammatory response.
While Inflammab represents a therapeutic breakthrough, McGilligan still had to figure out a way of delivering it to its target. “Antibodies are quite big,” she explains. “The disease we are targeting is inside the cell and we had to come up with a novel way of getting the antibodies inside them. We have developed a patented means of targeting a receptor on the outside of the cell and this acts as a ferry to carry the antibody in.”
This has the advantage of making it a two-in-one antibody in that it is biospecific and will only work on selected targets. “It attaches to a cell and the receptor turns itself inside-out and carries the antibody inside,” she adds.
The particular mechanism may have relevance for the battle against coronavirus. “I am working on a Covid-related area which might prove useful,” says McGilligan. “It we can target the enzyme on the outside of the cell that allows the virus get inside we might be able to stop the virus getting in.”
McGilligan and her team are looking for funding for the commercialisation of Inflammab at the moment. “We have completed proof of concept studies in pre-clinical models in glaucoma and cardiovascular disease and we are in the middle of setting up collaborations for multiple sclerosis and NASH (non-alcoholic steatohepatitis) a type of non-alcoholic fatty liver disease. We also want to drive forward into other disease areas.”
There are other small molecule therapies for many of these areas, but they have an extremely short half-life of about three hours. “Antibodies last much longer,” says McGilligan. “Patients wouldn’t have to go to hospital for treatment every day if they were using antibodies.”
The next step is to establish a spin-out company. “We are hoping to set that up very soon and we are interested in partnering opportunities to exploit this breakthrough. We are also looking for investors to fund the commercialisation of this important and fascinating therapy.”