ICF Targeting the extracellular matrix protease ADAMTS8 to treat fibrosis in pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a chronic, life-threatening disease characterised by high blood pressure (hypertension) in the vessels that bring blood from the heart to the lungs, leading to heart failure. The 5-year mortality rate is 50-65% and the average patient's survival time from diagnosis is less than 3 years. No cure exists for PAH, the treatment being limited to drugs that decrease hypertension. Ultimately, lung transplantation is needed. PAH is a relatively rare disease (4-55 cases/million people), but since it is difficult to diagnose, many more people may be affected. PAH severity and lack of therapeutic interventions cause massive distress to the patients and their relatives/friends. Costs associated to PAH management represent a significant burden to the NHS (£43.2M for the period of 2013-2017). It is therefore critical to develop agents able to halt or slow down its progression. A hallmark of PAH is the accumulation of proteins within the cardiac tissue, also called fibrosis, that severely impairs the ability of the organ to contract and work. Recently, a protein called ADAMTS8 has been identified as a detrimental factor in the progression of PAH: 1) ADAMTS8 levels are significantly increased in the lungs of PAH patients; 2) mice genetically modified to lack ADAMTS8 showed less cardiac and vascular fibrosis which ensured protection from severe PAH. ADAMTS8 belongs to a class of proteins called extracellular proteases, molecular scissors that cut other proteins in the space surrounding the cells, the extracellular matrix (ECM). Our preliminary data suggest that ADAMTS8 drives deleterious, profibrotic changes in the ECM, similar to the ones observed in PAH patients, and that ADAMTS8 must be proteolytically active to exert this effect. Therefore, targeting ADAMTS8 activity may be a novel approach to treat PAH. Unfortunately, no molecules able to block ADAMTS8 activity are currently available. Here, we propose to use the diversity of the AstraZeneca collection (library) of compounds to isolate molecules able to block ADAMTS8 activity. We will achieve this by testing 500,000 compounds in our assay where cleavage of a small synthetic substrate by ADAMTS8 generates a fluorescent signal. Inhibitors will be identified by their ability to block ADAMTS8 activity at least by 50%. The hits will be subsequently validated and tested in a number of assays involving use of natural substrates, direct binding to ADAMTS8, and their ability to decrease fibrosis in cultured human cardiac fibroblasts. We aim to end up with 5-10 molecules that can be subsequently optimised or directly tested in preclinical models of PAH to assess their antifibrotic effect. Given the lack of drugs for PAH, our project addresses a major gap in our ability to manage this severe, lethal disease by exploring a novel therapeutic target.