Mitochondrial dysfunction is associated with numerous cardiac disorders and progression to heart failure. Advantx‘s candidate ADV127 has been precisely designed to bind to Sigma-1 receptors on mitochondrial cell membranes and restore mitochondrial homeostasis.
Cardiovascular diseases encompass a diverse set of conditions that affect the heart and blood vessels, but whose cellular and molecular mechanisms are poorly understood. Mitochondrial dysfunction has been shown to be associated with numerous cardiac diseases, such as atherosclerosis, ischemia-reperfusion injury, heart failure, and hypertension, presumably due to insufficient cellular energy production and uncontrolled ROS production. Intercellular transfer of mitochondria is one of the natural mechanisms in mammals to recover mitochondrial dysfunction and restore respiration and survival of recipient cells.
The Sigma-1 receptor is a vital component of the mitochondria-associated endoplasmic reticulum membranes (MAM). Dysregulation of MAMs functions is correlated with the etiology of all cardiovascular diseases. Sigma-1 receptor plays a key role in maintaining physiological mitochondrial fuel substrates-linked respirations, key in cardiovascular diseases. Importantly, Sigmar1 also promotes mitochondrial transfer by enhancing the expression of CD38 and ERK1/2, improving cardiomyocyte bioenergetics and viability. Also contributes to relieving heart hypertrophy, ischemia‑reperfusion injury, atrial fibrillation, and heart failure. Activation of the receptor by a Sigma-1 agonist also alleviates the dysfunction of the right ventricle without affecting pulmonary artery pressure and remodeling, and modulates the interaction between Sigmar1 and CaV1.2 (regulated by α2δ-1 subunit), which also contributes to the beneficial effects of Sigma-1 activation on cardiomyocytes.
Potential market for Advantx candidate in Cardiovascular diseases
Prevalence>525m people globally
Treated Population>205m patients
Market Growthest. 4% CAGR
data from Globaldata
Differentiated Cardiovascular Disorders
A stroke occurs when blood flow to an area of the brain is interrupted. Brain cells, deprived of the oxygen and glucose needed to survive, die.
The most common type, ischemic stroke, is similar to a heart attack, except that it is caused by blockage of blood vessels in the brain. Blood–brain barrier (BBB) disruption is one of the most important pathological manifestations of ischemic stroke. Strokes can also be due to hemorrhagic strokes caused by high blood pressure or cerebral aneurysms that cause a blood vessel in the brain to rupture and blood to leak into the brain tissue, causing damage to brain cells.
Stroke leads to brain damage with subsequent slow and incomplete recovery of lost brain functions. The Sigma-1 receptor activation in cerebral microvascular endothelial cells (CMECs) ameliorated BBB post-ischemic stroke pathways and contributes to the formation of a milieu permissive for neuronal regeneration in the brain of stroke-injured patients.
Every 3.5 minutes, someone dies of a stroke in the United States. Every year, more than 795,000 people have a stroke.
PULMONARY ARTERIAL HYPERTENSION (PAH)
Pulmonary arterial hypertension (PAH) is a chronic disease characterized by a progressive elevation in mean pulmonary artery pressure, which leads to right heart failure and death. PAH is associated with pulmonary artery inflammation, abnormal remodeling, and increased right ventricular (RV) afterload. Oxidative stress increases in the lungs and contributes to PAH development. Elevated oxidative stress is found in the lungs of PAH patients compared with healthy controls. Oxidative stress has been suggested to play a pivotal role in pulmonary vascular remodeling, which in turn increases the right ventricle (RV) afterload, leading to RV hypertrophy and ultimately RV failure. Activation of Sigma-1 receptor directly improves right ventricular dysfunction, alleviates right ventricular remodeling, and reduces oxidative stress in right ventricular dysfunction. In the USA, mortality in patients with pulmonary arterial hypertension remains high, reaching 21% at 3 years.
ADV127 is Advantx’s candidate for the treatment of Stroke and Pulmonary Arterial Hypertension.