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.
Lumasiran是一种靶向羟基酸氧化酶1（HAO1）mRNA的特异性siRNA治疗药物[1]。Lumasiran与N-乙酰半乳糖胺（GalNAc）共价偶联，通过RNA干扰机制特异性沉默HAO1基因表达，阻断乙醇酸氧化酶（GO）的翻译过程[2]。GO是一种肝脏过氧化物酶，催化乙醇酸氧化为乙醛酸盐，是肝细胞中草酸盐合成的直接前体[3]。Lumasiran具有肝脏靶向性，通过与肝细胞高表达的去唾液酸糖蛋白受体（ASGPR）结合实现特异性递送[4]。Lumasiran通常用于原发性高草酸尿症1型（PH1）的研究[5][6]。
体内实验中，在AGXT敲低和乙二醇喂养引起的高草酸尿大鼠中，Lumasiran（3mg/kg/周；皮下注射；4周）导致编码乙醇酸氧化酶的mRNA有效、剂量依赖性和持久的沉默，并使尿草酸浓度降低98%[7]。