Discovering significant breakthroughs in fibrosis.
Blade is developing innovative approaches to understand the underlying disease and treat fibrosis.
Uncontrolled, progressive fibrosis is a driving factor in organ dysfunction of many debilitating disease states, afflicting millions of individuals in the United States and worldwide. Fibrosis-related diseases can affect organs including the liver, lung, skin, kidney and eye, leading to organ dysfunction and failure, and potentially death.
While the underlying pathophysiology of fibrosis is complex, research continues to enhance our understanding of the disease processes. Some common components of the pathophysiology of fibrotic diseases are known, as represented below. Activation/differentiation of myofibroblast cells is recognized as a central step leading to the production of extra cellular matrix (ECM). The replacement of normal cellular-tissue architecture by progressive deposition of ECM (fibrosis) by myofibroblasts leads to organ dysfunction. Expression of alpha-smooth muscle actin (aSMA) and Collagen 1A1 (Col 1) are early markers of myofibroblast cell activity. There is a pressing need to identify targets and develop new therapies against those novel targets and pathways that can arrest and reverse this process.
Blade’s lead program, BLD-2660, was developed by leveraging insights from John Hopkins University School of Medicine (Laboratory of Hal Dietz, M.D.) to discover new therapeutic approaches that can broadly modulate fibrosis, and thereby contribute to the treatment of diverse diseases.
BLD-2660 is specifically designed to target a group of neutral proteases, the so-called dimeric calpains (calpain 1, 2 and 9), which are part of larger family of calpain proteases, of which there are ~15 members. In pre-clinical models, inhibiting the activity of dimeric calpains has been shown to be beneficial to stop progression or reverse fibrosis in several organs and acts at the early stages of myofibroblast activation/differentiation. Data generated by Blade and others demonstrate that inhibition of the dimeric calpains has a direct anti-fibrotic effect in multiple organ systems.
Autotaxin is a secreted enzyme that catalyzes the hydrolysis of lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA), a bioactive phospholipid. LPA action is exerted through its binding to specific G-protein-coupled receptors, LPA1-6, resulting in the initiation of multiple signaling cascades, such as calcium mobilization, activation of Ras, and extracellular-signal-regulated kinase (ERK) pathways. The activation of these pathways has an effect on cell survival, cytoskeletal remodeling, as well as migration, and endothelial permeability. LPA receptors are differentially expressed in different tissues and cell types.
LPA/ATX axis has been linked to the pathogenesis of fibrosis in several organs. Decrease LPA activity has been shown to be beneficial in models of liver, kidney, lung and skin fibrosis. Additionally, increased levels of ATX and LPA have been measured in chronic diseases including IPF, fibrotic liver disease, and rheumatoid arthritis. In clinical studies, inhibition of ATX or LPA1 has shown promise in slowing disease progression in IPF patients.
Diseases characterized by uncontrolled, progressive fibrosis include idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), systemic sclerosis (SSc) .
Idiopathic Pulmonary Fibrosis (IPF)
Idiopathic pulmonary fibrosis (IPF) is a rare, highly debilitating, and poorly understood disease. Most commonly affecting individuals over 50 years old, IPF is characterized by interstitial pneumonia and chronic progressive lung fibrosis. Over the course of the disease, healthy lung tissue is replaced with fibrotic tissue, causing a continuous decline in lung function. Disease progression is unpredictable and is often rapid, with many patients progressing to lung failure and potentially death within 2 - 3 years. Unfortunately, the disease’s early genesis is unknown, and there are no tests to identify patients that are at greatest risk of developing IPF. Members of Blade’s own team were instrumental in the pioneering work at InterMune that led to the approval of pirfenidone to treat IPF; however, there remains a pressing need for effective therapies for this serious and as-of-yet incurable disease.
Non-Alcoholic Steatohepatitis (NASH)
It is estimated that up to one-third of the populations in the US and Europe have a condition termed non-alcoholic fatty liver disease (NAFLD), which is characterized by steatosis, or excessive accumulation of fat in the liver (Wree, 2013; Blachier, 2013). Many of these individuals, for reasons not totally understood, subsequently develop liver inflammation, or steatohepatitis. This condition, called non-alcoholic steatohepatitis, or NASH, develops in roughly 10 - 20% of NAFLD patients, accounting for approximately 10 - 20 million individuals in the US (Schattenburg, 2011). Individuals experiencing chronic liver inflammation often develop liver fibrosis, with eventual risks of cirrhosis, hepatocellular carcinoma, and liver failure. Based on current projections, NASH is predicted to become the leading cause of liver transplantation by 2020 (Wree, 2013). Unfortunately, there are no therapies available to prevent or treat liver fibrosis.
Primary Sclerosing Cholangitis (PSC)
Primary sclerosing cholangitis (PSC) is a rare, chronic, progressive disease characterized by inflammation and subsequent destruction of intra- and extrahepatic bile ducts. Over time, patients develop liver fibrosis and cirrhosis, which ultimately can lead to liver failure. PSC is also associated with increased rates of colorectal, hepatobiliary, and gallbladder cancer (Kumar, 2016). Epidemiology studies indicate that there may be up to 50,000 individuals afflicted with PSC in the US (Ali, 2015), although prevalence rates are generally presumed to be underestimated due to the difficulty of correctly diagnosing asymptomatic patients (Eksteen, 2014). Disease management primarily entails symptomatic treatment (for example, of pruritus and fatigue), but there are no FDA-approved agents to treat PSC, and no therapies have been shown to consistently slow disease progression. An anti-fibrotic agent that effectively delays disease progression would be of tremendous benefit to individuals with PSC.
Systemic Sclerosis (SSc)
Systemic sclerosis (SSc), or scleroderma (which translates to hardening of the skin), is a rare, chronic autoimmune disease characterized by fibrotic and vascular abnormalities. Most individuals with SSc exhibit some degree of skin fibrosis, although many patients also progress to develop fibrosis within internal organs, potentially leading to severe complications and organ failure. Disease progression is highly variable in SSc, with some patients remaining stable for years and others developing severe complications relatively rapidly. The underlying biology in SSc is complicated and poorly understood, which has hampered efforts to develop effective and curative therapies. Disease management is predominantly through patient-specific symptomatic interventions and systemic immunosuppression, neither of which are curative. An effective anti-fibrotic therapy could prolong organ function and offer tremendous benefit for SSc patients.
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Poly Q diseases are a family of currently incurable and mostly autosomal dominant neurodegenerative diseases. They result from mutations causing expansion of trinucleotide (CAG) repeat region of genes. In the case of Huntington’s Disease, the mistake is in the huntingtin (HTT) IT15 gene. In mutant Htt, the polyglutamine tract encoded by this region contains over 35 glutamines and encodes an abnormal HTT protein. These mutant proteins are burdened by toxic gain-of-function and aggregation properties.
Calpains are known to inhibit autophagy by clearing key proteins. Strategies that reduce calpain activity in vitro have been demonstrated to increase autophagy and decrease levels of autophagy substrates, like mutant Htt. The Blade strategy is to inhibit calpain activity to harness the cell’s capacity to degrade mutant aggregate-prone proteins via autophagy. Mutant polyglutamine expanded proteins (including mutant HTT, tau, and mutant ataxin 3) are autophagy substrates. In animal models, clearance by enhanced autophagy has been shown to reduce toxicity.