Inflammatory responses from protease-activated receptors (PARs) have recently been implicated in numerous disease states, and modulation of PAR signaling with various molecules is a promising approach to dampening inflammation and increasing protective signaling. Function Therapeutics and our collaborators (see Science page) are working to understand PAR signaling in greater detail and leverage it for the treatment of several conditions with high unmet medical need:
Chronic Kidney Disease
Chronic and acute kidney diseases are estimated to afflict >14% of the population, and are characterized by an inability to excrete metabolic waste efficiently through the urine. Chronic kidney disease (CKD) usually involves a gradual but presently irreversible decline in kidney function, which may ultimately end in kidney failure, a leading cause of death. The validation of new targets for the treatment of kidney disease is urgently needed. One promising target involved in the adverse inflammatory state of cells in diseased kidneys is protease-activated receptor 1 (PAR1). The lab of our SAB member Dr. Berend Isermann (Leipzig University) confirmed that our 1st-generation PAR1-targeting compound (parmodulin) ML161 was effective in substantially improving kidney function in a mouse model of diabetic nephropathy. Next-generation parmodulins are slated for advanced preclinical studies that ultimately aim to validate that biased ligands of PAR1 can safely improve kidney function in patients suffering from acute or chronic kidney disease.
Acute Kidney Injury
Acute kidney injury (AKI) is the sudden and dangerous loss of kidney function that causes significant morbidity and mortality. A significant fraction of patients undergoing major surgery suffer from AKIs, particularly cardiac patients, with >10% probability of AKI frequently reported. Almost half of hospitalized COVID patients suffered from dangerous (and often deadly) AKIs early in the pandemic, and certain anti-cancer therapies and anti-infectives are known to cause AKIs. AKIs extend hospitalization, and even when kidney function returns to more normal levels, patients suffering from AKIs are at much greater risk of developing chronic kidney disease. Presently, there are no drugs approved by the FDA for the prevention of AKI. Building upon prior studies with activated protein C (APC), Function Therapeutics is leading preclinical investigations into the use of PAR1-targeting parmodulins to protect kidney cells and prevent AKI during inflammatory conditions, such as those present during bypass surgery or severe infection.