Primary hyperoxaluria (PH) is a rare autosomal recessive genetic disorders accompanied by overproduction of oxalate in the liver. Meanwhile, lactate dehydrogenase (LDH) is an enzyme responsible for conversion of glyoxylate to oxalate, which is the final step in the oxalate synthesis pathway. Therefore, one emerging therapeutic strategy for primary hyperoxaluria is to reduce oxalate level by inhibiting LDH. Besides, RNA interference (RNAi) is a biological pathway for silencing gene expression. The advantage is to reduce the proteins that cannot be easily targeted by small molecules.
Nedosiran (DCR-PHXC), a FDA-approved compound for primary hyperoxaluria, is a RNA interference (RNAi) targeting LDH. Structurally, Nedosiran is a GalNAc-dsRNA conjugate. GalNAc enables Nedosiran to specifically bind to asialoglycoprotein receptor (ASGPR) and has liver-specific targeting ability.
Nedosiran, a GalNAc-dsRNA conjugate, is an RNA interference (RNAi) targeting LDH for primary hyperoxaluria research.
Specifically, Nedosiran is a synthetic, double-stranded RNA oligonucleotide, and targets the mRNA encoding LDHA. By binding to ASGPR located in hepatocytes, Nedosiran can specifically inhibit hepatic LDH level. Nedosiran is usually administered by subcutaneous injection. Importantly, Nedosiran is able to decrease plasma oxalate in animal models, and has no apparent adverse effects in off-target (nonhepatic) tissues. Therefore, Nedosiran has great potential for research of primary hyperoxaluria, including 3 genetically defined types of PH (PH1, PH2, and PH3).