Lumasiran is a specific siRNA therapeutic targeting hydroxyacid oxidase 1 (HAO1) mRNA[1]. Covalently conjugated with N-acetylgalactosamine (GalNAc), Lumasiran specifically silences HAO1 gene expression through an RNA interference mechanism, blocking the translation of glycolate oxidase (GO)[2]. GO is a hepatic peroxisomal enzyme that catalyzes the oxidation of glycolate to glyoxylate, the immediate precursor for oxalate synthesis in hepatocytes[3]. Lumasiran has liver targeting and achieves specific delivery by binding to the highly expressed assialoglycoprotein receptor (ASGPR) in hepatocytes[4]. Lumasiran is usually used in the study of primary hyperoxaluria type 1 (PH1)[5][6].
In vivo, Lumasiran (3mg/kg/week; subcutaneous injections for 4 weeks) resulted in potent, dose-dependent, and durable silencing of the mRNA encoding glycolate oxidase and reduced urinary oxalate concentration by 98% in rats with hyperoxaluria induced by AGXT knockdown and ethylene glycol feeding[7].
References:
[1] Scott LJ, Keam SJ. Lumasiran: First Approval. Drugs. 2021;81(2):277-282.
[2] Garrelfs SF, Frishberg Y, Hulton SA, et al. Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1. N Engl J Med. 2021;384(13):1216-1226.
[3] Hoppe B, Martin-Higueras C. Improving Treatment Options for Primary Hyperoxaluria. Drugs. 2022;82(10):1077-1094.
[4] D'Ambrosio V, Ferraro PM. Lumasiran in the Management of Patients with Primary Hyperoxaluria Type 1: From Bench to Bedside. Int J Nephrol Renovasc Dis. 2022;15:197-206.
[5] Gang X, Liu F, Mao J. Lumasiran for primary hyperoxaluria type 1: What we have learned?. Front Pediatr. 2023;10:1052625.
[6] Hulton SA, Groothoff JW, Frishberg Y, et al. Randomized Clinical Trial on the Long-Term Efficacy and Safety of Lumasiran in Patients With Primary Hyperoxaluria Type 1. Kidney Int Rep. 2021;7(3):494-506.
[7] Liebow A, Li X, Racie T, et al. An Investigational RNAi Therapeutic Targeting Glycolate Oxidase Reduces Oxalate Production in Models of Primary Hyperoxaluria. J Am Soc Nephrol. 2017;28(2):494-503.