MICA: Myeloperoxidase inhibition as a potential therapy in anti-neutrophil cytoplasmic antibody vasculitis

Antibodies are circulating proteins in the immune system that normally fight infection. The immune system can malfunction and in some patients antibodies stick to white blood cells and cause a form of vasculitis or blood vessel inflammation. This can affect joints, lungs, kidneys, skin and other tissues and occurs most often in older adults. The antibodies bind in particular to the proteins myeloperoxidase (MPO) proteinase 3 which are found in certain white blood cells. The antibodies are thought to play a key role in causing disease. MPO is a protein in white blood cells that normally fights infection and can also cause tissue inflammation in certain diseases. Thus blocking MPO may be beneficial in inflammatory disease such as vasculitis. The proposed study will define whether the MPO inhibitor AZD5904 is effective in reducing disease onset and/or development, and elucidate potential mechanisms. Our hypothesis is that inhibition of MPO enyzme activity will be an effective therapy for vasculitis. Using the MPO inhibitor AZD5904, we plan to test this through a combination of experiments using human and murine white blood cells in vitro and murine in vivo models. In the first part of the research, we will use an in vivo model of anti-MPO vasculitis in mice. In addition to examining the therapeutic efficacy of AZD5904 we will explore the mechanisms of this effect with particular reference to the same type of white blood cell that will be studied in the in vitro work with patient samples. We will also aim to understand the effect of anti-MPO antibody, purified from the blood of patients with vasculitis, on human white blood cells. Our preliminary data suggest important effects on the responses of a particular type of white blood cell that are relevant to disease. We aim to understand the mechanism by which these effects depend on MPO enzyme, and to link this to potential consequences for disease expression in the murine model. This will place us in an ideal position to proceed to clinical trials and this would naturally follow from the plan of work contained in the current application.

ANCA vasculitis a severe systemic disease which affects joints, lungs, kidneys, skin and other tissues. It occurs most often in older adults. Autoantibodies against the neutrophil and monocyte antigens myeloperoxidase (MPO) and proteinase 3 are found in patients and in vitro and in vivo data suggest that these play a key role in pathogenesis. Our hypothesis is that inhibition of MPO enzyme activity will be an effective therapy for ANCA vasculitis via effects on both neutrophils and monocytes. We plan to test this through a combination of experiments using human monocytes in vitro and murine in vivo models. The in vivo model will include the murine model of anti-MPO vasculitis in which crescentic glomerulonephritis is induced by injection of anti-MPO antibodies raised in MPO deficient mice. In addition to establishing the potential of this approach for therapy, we will explore some novel mechanisms by which MPO inhibition may affect monocyte cell function.

The combination of in vitro experiments with patient samples and in vivo experiments in a preclinical model will provide a comprehensive picture of the potential of AZD5904 as a therapy in anti-MPO vasculitis. Since AZD5904 is an orally available agent, with clinical safety data are available, this rational and comprehensive experimental design will facilitate rapid translation.

Close communication between the academic and industry further facilitate rapid translation and the development of a clinical trial to follow on from this work.
The results of the work will be presented at medical and scientific conferences and published in peer-reviewed journals.

This proposal may in time lead to the development of more specific and less toxic therapies for glomerulonephritis and ANCA vasculitis in particular. Benefits to patients such as increased survival and improved quality of life are the ultimate aims of this research. This may result from more specific therapy such as AZD5904 which will have less toxicity than exisiting therapies. This will reduce the cost of treatment complications, and the burden of dialysis and transplantation.

We have regular communication with our Kidney Patients Association and patients will be invited to help in planning any clinical trials. The general public perception of glomerulonephritis and vasculitis is limited, and there is a particular need for early diagnosis and treatment in these conditions. This study and the potential development of a clinical trial will increase this awareness.