Discovering significant breakthroughs in fibrosis.
OUR SCIENCE
Blade is founded on a commitment to revolutionize the treatment of debilitating fibrotic diseases.
Fibrosis is a complex, pathologic process characterized by the thickening or scarring of organ tissue in response to cell/tissue damage or inflammation. Once afflicted, the tissue no longer functions normally. Fibrosis may overwhelm organs that include the liver, lung, skin, kidney, joints and eye. Fibrotic diseases are incurable, impairing the lives of millions of people worldwide.
While the underlying pathophysiology of fibrosis is complex, research continues to enhance our understanding of the disease processes. At Blade, we are experts in novel biological pathways – including autotaxin / LPA and calpain biology – that are foundational to cell and tissue damage responses leading to fibrosis.
Autotaxin / LPA and calpains each play distinct roles within the biological pathways underlying fibrosis. Ongoing dysregulation of those pathways underlies the progression and severity of fibrosis and resulting organ dysfunction.
Pro-fibrotic processes are stimulated by autotaxin, a key enzyme that plays a complementary role to calpains in various fibrotic diseases.
Autotaxin regulates the production of lysophosphatidic acid (LPA) that can become over-activated in response to aberrant signaling or cell damage. Both autotaxin and LPA are produced in response to inflammation to mediate wound repair (cicatrization). View the graphic below for a step-by-step explanation.
Role of Autotaxin in Fibrosis
Injury / Damage in Epithelium Fibrosis is triggered by an injury that damages epithelial cells (epithelium).
Dysregulated Cell / Tissue Damage Response Dysregulated cell / tissue damage response in the epithelium can lead to increased levels of autotaxin and its product lysophosphatidic acid (LPA)
Release of Pro-fibrotic Mediators LPA binds to LPAR1 – its receptor on fibroblasts – and triggers a signaling cascade that results in fibroblast migration, activation and release of mediators
LPA activates Myofibroblasts LPA is required for activation of myofibroblast cells.
Extracelluar Matrix Production Myofibroblasts secrete extracellular matrix (scarring) that disrupts normal organ architecture and function.
The autotaxin / LPA axis impacts development of disease, with aberrant LPA signaling linked to broad range of pathophysiological conditions. Increased autotaxin levels and activity are associated with liver, lung, kidney and skin fibrosis. Inhibition of the autotaxin / LPA receptor pathway has been clinically validated in idiopathic pulmonary fibrosis (IPF) and in scleroderma. In addition, autotaxin levels correlate with fibrosis severity in various liver diseases (NAFLD / NASH, viral hepatitis, ALD, cirrhosis).
More about our Science
References
Stoddard, 2015, Biomol Ther. 23(1):1.
Matralis, 2019, Med Res Rev. 39(3):976.
Maher, 2018, Lancet Resp Med. 6(8):627.
Palmer, 2018, Chest. 154(5):1061.
Galapagos company news release. 10 Sept 2020.