Fibrosis or scarring is the deposition of connective tissue rather than normal parenchymal tissue as part of wound healing. Fibrosis can occur during severe injuries and inflammation or can be genetically inherited. Genetic fibrotic conditions include idiopathic pulmonary fibrosis, cystic fibrosis, systemic sclerosis and more.
Systemic sclerosis is a progressive, rare disease that causes fibrosis not only in the skin but also in tissues throughout the body, including the heart, lungs and kidneys. Pulmonary disease is a complication that has a particularly high incidence, and interstitial pneumonia has been reported as a major cause of death in patients with systemic scleroderma. Currently, there is no curative treatment for systemic sclerosis, only symptomatic treatment of skin and lung symptoms.
Systemic sclerosis is often considered a Th2 cytokine disease characterized by increased type 2 cytokines, including IL-4, IL-5, and IL-13 and eosinophil infiltration. Prostaglandin D2 through the DPr2 receptor is known to induce activation of the type 2 allergic immune response during allergic diseases by activating Th2 cells and eosinophils (Domingo et al, Respiratory Research, 2018). Eosinophilia is associated with the severity of systemic sclerosis (Ando et al, SpringerPlus, 2016). Ramatroban, by blocking the DPr2 receptor, suppresses production of type 2 cytokines and eosinophil migration (Xue et al, J Immunol, 2005 ; Ishizuka et al, Cardiovascular Drug Reviews, 2006), thereby potentially ameliorating fibrosis during systemic sclerosis. Eosinophils have also been implicated in a number of other type 2 inflammatory diseases including allergic rhinitis, atopic dermatitis, idiopathic pulmonary fibrosis, Churg-Strauss syndrome (eosinophilia granulomatosis and polyangiitis, eosinophilic oesophagitis and hypereosinophilic syndrome, all of which can be potentially treated with Ramatroban (Brightling et al, Allergy, 2020).
Late stage systemic sclerosis is characterized a loss in angiogenesis which is the ability of blood vessels to regenerate. A loss of angiogenesis can starve the tissues of oxygen necessary for normal repair leading to tissue damage and fibrosis. Normally, angiogenesis is regulated by growth factors such as vascular endothelial growth factor which promote new blood vessel growth. However, in systemic sclerosis, 8-isoprostane, generated during oxidative stress stimulates the thromboxane receptor (TPr) to inhibit angiogenesis (Tsou et al, J Invest Dermatol, 2015). TPr antagonism with Ramatroban in systemic sclerosis may restore angiogenesis and perfusion to the tissues, thereby reducing fibrosis.
A common complications of systemic sclerosis is pulmonary arterial hypertension due to vasoconstriction of the pulmonary arteries. Blockade of the thromboxane receptor (TPr) with Ramatroban increases production of nitric oxide which promotes vasodilatation (Shiokoshi et al, J Hypertens, 2002), potentially preventing pulmonary hypertension.
Apoptosis, or programmed cell death occurs to clear old tissue and promote wound healing. However, apoptosis often precedes fibrosis and has been identified as a key player in the initiation, propagation and resolution of organ fibrosis including liver and lung fibrosis, and cardiac allograft, chronic transplant and renal allograft vasculopathy (Johnson and DiPietro, FASEB J, 2013).
Prostaglandin D2 exerts its functions on two receptors, the DPr1 and the DPr2 receptors. While DPr1 promotes survival, the DPr2 receptor induces apoptosis of a variety of cells including cardiomyocytes (Zuo et al, EMBO, 2018), islet cells (Abadpour et al, Diabetologia, 2020), osteoclasts (Yue et al, Bone, 2012) and renal tubule cells (Maesaka et al, Semin Nephrol, 2002), indicating a role for prostaglandin D2/DPr2 axis in the progression of heart disease, type I diabetes, osteopetrosis and kidney disease, respectively. Prostaglandin D2 induced apoptosis may be prevented with DPr2 antagonism by Ramatroban.
Thromboxane A2 is well-known for its role in cardiovascular disease and cell immunity including platelet activation. Additionally, thromboxane induces thymocyte apoptosis leading to impaired adaptive immune response (Ushikubi et al, J Exp Med, 1993). The apoptotic effects of thromboxane are further described below.
Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by genetic alterations in the protein dystrophin which helps to keep muscle cells intact. Currently, there is no cure for DMD.
Currently, a selective TPr antagonist is in phase 2 clinical trials for treatment of DMD. Preclinical studies with a TPr antagonist have demonstrated great benefit in DMD dilated cardiomyopathy (West et al, J Am Heart Assoc, 2019). TPr antagonism was shown to markedly improved survival rates in three mouse models of muscular dystrophy (severe DMD, DMD with shortened telomeres and limb-girdle muscular dystrophy). In both models of DMD, TPr antagonism increased cardiac index and stroke volume. In the limb-girdle muscular dystrophy model, which developed dilated cardiomyopathy with diffuse fibrosis, TPr antagonism prevented: (1) decline in ejection fraction and fractional shortening; (2) elevation in left ventricular systolic pressure; (3) myocardial fibrosis; (4) decline in cardiomyocyte and whole heart remodeling and function; (5) reduced protein levels of neuronal nitric oxide synthase and tight junctional protein claudin-5.
In a widely used mouse model of DMD, acetylcholine induced vasodilatation is impaired leading to increased vasoconstriction. TPr antagonism reversed enhanced coronary artery vasoconstriction in young DMD mice, thus allowing perfusion to the heart (Mitchell et al, Am J Physiol Heart Circ Physiol, 2021).
Prostaglandin D2 plays a role in muscle necrosis and is high in DMD (Mohri et al, Am J Pathol, 2009). Prostaglandin D2 via the DPr2 receptor induces cardiomyocyte apoptosis (Zuo et al, EMBO, 2018), potentially inducing cardiac fibrosis in DMD.
Ramatroban targets both the thromboxane A2/TPr and prostaglandin D2/DPr2 receptors, thus having great potential in ameliorating DMD cardiomyopathy and cardiac fibrosis.