TRPC6 for Kidney Disease
Algomedix is developing a TRPC6 antagonist – a first-in-class, oral, small molecule therapeutic candidate for the treatment of chronic kidney disease.
Utilizing its novel TRP drug discovery approach and research capabilities, Algomedix is advancing a small molecule TRPC6 antagonist for the treatment of chronic kidney disease.
More than 50 million adults in the United States and Europe suffer from chronic kidney disease with millions more at increased risk of acquiring the disease. Chronic kidney disease – the gradual loss of kidney function – can be acquired or hereditary. Diabetes is the most common cause of kidney disease, also termed diabetic nephropathy. In addition, gain-of-function mutations in the TRPC6 gene are a cause of autosomal dominant focal segmental glomerular sclerosis (FSGS), which is also a progressive kidney disease. There is no cure for chronic kidney disease and no therapeutics are available that can reverse progression of disease. Existing treatments to manage or attempt to slow the progression of chronic kidney disease include the use of non-specific drugs to lower blood pressure. However, patients often progress to end-stage renal disease which requires either kidney dialysis or renal transplantation.
TRPC6 Antagonist Advantages
TRPC6 is a validated target expressed on podocytes – a critical target cell in the kidney that controls renal filtration. Evidence indicates that TRPC6 plays an important role in podocyte function.
The TRPC6 receptor-channel functions as a cation channel found on the surface of the podocyte membrane. Functional deficiencies or injuries to podocytes adversely affect kidney function and contribute to diabetic nephropathy and other kidney diseases. Over-activation of TRPC6 leads to increased protein in the urine (proteinuria), a clinical feature of many types of kidney disease.
As shown in the figure below, Angiotensin II (Ang II) which is a peptide hormone in the body, upon binding to its G-protein-coupled receptor (AT1R), results in activation of TRPC6 in podocytes.
TRPC6 Antagonist Data
Algomedix has generated preclinical data supporting the novel mechanism of action of its TRPC6 small molecule candidate. This therapeutic candidate has been shown to directly and potently inhibit TRPC6 in podocytes and in isolated kidney ex vivo studies. Studies have also demonstrated the ability of the antagonist to block Angiotensin II stimulation of TRPC6 downstream signaling in podocytes. These studies indicate the potential for sustained therapeutic beneficial effects under chronic conditions.