What is the mechanism of Nedosiran?

Nedosiran is a promising therapeutic agent currently under investigation for the treatment of primary hyperoxaluria, a group of rare genetic disorders characterized by the overproduction of oxalate, a substance that can lead to kidney stones and other serious complications. The mechanism of action of Nedosiran is rooted in the principles of RNA interference (RNAi), a natural cellular process that regulates gene expression.

Primary hyperoxaluria (PH) is primarily caused by mutations in genes that encode enzymes necessary for glyoxylate metabolism. These mutations lead to an accumulation of oxalate, which combines with calcium to form calcium oxalate crystals. Over time, these crystals can deposit in the kidneys and urinary tract, leading to kidney stones, nephrocalcinosis, and eventually kidney failure if left untreated.

Nedosiran specifically targets the hepatic lactate dehydrogenase (LDH) enzyme, which plays a critical role in the conversion of glyoxylate to oxalate. By inhibiting this enzyme, Nedosiran aims to reduce the production of oxalate at its source.

The RNAi mechanism through which Nedosiran operates involves small interfering RNA (siRNA) molecules. These siRNA molecules are designed to be complementary to the messenger RNA (mRNA) that encodes the LDH enzyme. Once administered, Nedosiran is taken up by liver cells, where it employs the cell's own RNAi machinery to degrade the specific mRNA associated with LDH. This degradation process effectively silences the expression of the LDH enzyme, thereby reducing the conversion of glyoxylate to oxalate.

The reduction in oxalate production can lead to a significant decrease in urinary oxalate levels, which is the primary therapeutic goal for patients with primary hyperoxaluria. Lower urinary oxalate levels can reduce the risk of kidney stone formation and other associated complications, improving the overall quality of life for these patients.

Preclinical studies and early clinical trials of Nedosiran have shown promising results, demonstrating a significant reduction in urinary oxalate levels in patients with various subtypes of primary hyperoxaluria. The specific targeting of the LDH enzyme by Nedosiran provides a novel and targeted approach to managing this challenging condition.

In summary, Nedosiran represents a significant advancement in the treatment of primary hyperoxaluria by leveraging RNA interference to inhibit the hepatic LDH enzyme, thereby reducing oxalate production at its source. This targeted mechanism of action has the potential to provide meaningful clinical benefits to patients suffering from this rare and debilitating disorder.