Dicerna’s lead investigational RNAi therapy in development for the treatment of PH
We are developing nedosiran, our most advanced RNAi drug candidate utilizing our proprietary GalXC™ RNAi technology for the treatment of primary hyperoxaluria (PH). PH is a family of ultra-rare, life-threatening genetic disorders that initially manifest with complications in the kidneys. Nedosiran is designed to inhibit production of the hepatic lactate dehydrogenase (LDH) enzyme – an enzyme involved in the conversion of glyoxylate to oxalate. Patients with PH have an overproduction of oxalate which can lead to kidney stones and chronic kidney disease, among other complications. Dicerna is evaluating the safety and efficacy of nedosiran in patients with all known types of PH as part of its PHYOX™ clinical development program.
Preventing excess oxalate production
There are three known types of PH (PH1, PH2 and PH3), each resulting from a mutation in one of three different genes in the glyoxylate metabolism pathway: AGXT, GRHPR and HOGA1 respectively. Abnormal production and accumulation of oxalate leads to recurrent kidney stones, nephrocalcinosis and chronic kidney disease that may progress to end-stage kidney disease requiring intensive dialysis and systemic deposition of oxalate in various tissues in the body including the retina, bones, cardiac muscle and elsewhere. Nedosiran is designed to inhibit the production of hepatic lactate dehydrogenase (LDH) enzyme in the final common step of this pathway with the goal of preventing this overproduction of oxalate. This LDH enzyme inhibition occurs specifically in the liver due to the incorporation of GalNAc-targeting ligands in nedosiran that bind specifically to the asialoglycoprotein receptors (ASGPR) on hepatic cell surfaces.