Technology
CalciMedica's proprietary technology targeting CRAC channel inhibition for inflammatory diseases of high unmet need
CRAC Channel Over-Activation Causes an Inflammatory Immune Response
An essential messenger for intracellular signals, calcium plays diverse and important roles. Among other activities, it regulates biological processes such as nerve signal transmission, muscle contraction, inflammation, vascular permeability and cell death. The storehouse for calcium in a cell is a compartment called the endoplasmic reticulum (ER).
Calcium Release-Activated Calcium (CRAC) channels serve to replenish calcium levels in the ER and provide calcium for cellular signaling events. CRAC channels are found on many cell types including T-cells, pancreatic acinar cells, and the lung endothelium.
When an outside signal stimulates a cell, the stored calcium is rapidly released from the ER in a pulsatile manner into the cell interior, resulting in activation of several key processes affecting synthesis of other signaling molecules, cell growth, differentiation, and division. In response to external stress on the cell, release of calcium from these intracellular stores activates CRAC channels, causing even more calcium to move into the cell, and this calcium overload can trigger cell damage.
Inhibiting CRAC Channels may provide therapeutic benefit in inflammatory diseases
Inflammatory diseases including AP, respiratory failure, and kidney injury, are associated with the overactivation of CRAC channels, resulting in excess calcium entry that is toxic to cells, causing cellular injury or death that can exacerbate an accompanying inflammatory response.
In preclinical studies, CalciMedica has shown a clear link between CRAC channel activation and a broad spectrum of acute and chronic illnesses that have inflammation in their pathogenesis.
The inhibition of CRAC channels has the potential to modulate the immune response and protect against tissue cell injury. The goal of CalciMedica’s development programs is to explore the therapeutic benefits of CRAC channel inhibitors in inflammatory diseases of the pancreas, kidney and lung.
The effects of CRAC channel over-activation in acute pancreatitis
Excessive signaling through calcium-dependent pathways has been linked to multiple pathologies associated with acute pancreatitis (AP). A primary function of the pancreas is to produce enzymes that are required to digest food. The secretion of these enzymes from the pancreas is dependent on the periodic release of calcium from internal stores in the cells called the pancreatic acinar cells. In AP, aberrant activation of these cells results in elevated, toxic levels of intracellular calcium and consequently, the inappropriate activation of digestive enzymes inside the cells causes the acinar cells to self-digest.
Acute pancreatitis is also associated with a high level of inflammation. In some patients, the release of inflammatory cytokines and the triggering of systemic inflammatory response syndrome (SIRS) can lead to life-threatening distal organ failure. The most frequent systemic complications in severe cases of AP are respiratory dysfunctions ranging from hypoxemia to acute respiratory distress syndrome (ARDS). As in the case with ARDS from other underlying causes, AP-associated ARDS is the result of both increased vascular permeability and an increase in inflammation, which suggest being CRAC channel-dependent processes.