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| 1mg |
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| Other Sizes |
| Targets |
HAO1 (hydroxyacid oxidase 1, encoding glycolate oxidase). Lumasiran is an siRNA that targets the HAO1 messenger RNA (mRNA). By binding to the HAO1 mRNA, it triggers RNA interference-mediated degradation of the transcript, reducing the expression of the glycolate oxidase (GO) enzyme. Glycolate oxidase is responsible for the oxidation of glycolate to glyoxylate. By depleting glycolate oxidase, lumasiran inhibits the synthesis of oxalate, the toxic metabolite directly associated with the clinical manifestations of PH1. This mechanism reduces oxalate overproduction in the liver.
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| ln Vitro |
The cause of progressive renal injury in PH1 is urinary oxalate excretion, which is decreased by lumasiran [1].
Cell-free assays are not applicable for a siRNA therapeutic like lumasiran, as its activity depends on the endogenous RNA-induced silencing complex (RISC). However, its potency is assessed in cellular systems by transfecting hepatocyte cell lines (e.g., Huh-7, HepG2) with the siRNA and measuring HAO1 mRNA knockdown by qRT-PCR and glycolate oxidase protein by Western blot. The EC50 for HAO1 mRNA knockdown is typically in the low picomolar to nanomolar range. Lumasiran does not bind to protein targets directly; it hybridizes with specific complementary mRNA sequences. Specificity is confirmed by bioinformatics analysis of the siRNA seed sequence against the human transcriptome. |
| ln Vivo |
Lumasiran is an RNA interference (RNAi) twin that is targeted subcutaneously [2].
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| Enzyme Assay |
Lumasiran is an RNAi therapeutic, not a small molecule, so it is not used in standard cell-free enzyme assays. Instead, its mechanism of action is demonstrated in primary human hepatocytes. Cells are treated with lumasiran (diluted in Opti-MEM with a transfection reagent) for 24-48 hours. The reduction in HAO1 mRNA is measured by qRT-PCR, normalized to a housekeeping gene (e.g., GAPDH). The reduction in glycolate oxidase protein is measured by Western blotting. The functional consequence is measured by a decrease in oxalate production in the cell culture medium, determined by enzymatic assay or LC-MS/MS. Lumasiran is highly potent, with sub-nanomolar EC50 values for target knockdown. The GalNAc conjugation enables uptake by hepatocytes via the asialoglycoprotein receptor (ASGPR).
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| Cell Assay |
The activity of lumasiran in cell culture is typically evaluated in primary human hepatocytes or a hepatocyte cell line (e.g., Hep3B, Huh-7) that expresses ASGPR and HAO1. Cells are seeded in 96-well or 24-well plates and allowed to attach overnight. Lumasiran, often complexed with a lipid-based transfection reagent (e.g., Lipofectamine 2000) for delivery, is added at concentrations ranging from 0.0001-100 nM. For unconjugated siRNA, transfection is required. For the GalNAc-conjugated version (which mimics the drug), it can be taken up via ASGPR without transfection, though uptake may be enhanced. After 24-72 hours, cells are lysed, and HAO1 mRNA is quantified by qRT-PCR using TaqMan probes. The percent knockdown relative to a negative control siRNA is calculated, and the EC50 is determined. Protein levels are confirmed by Western blot.
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| Animal Protocol |
In vivo activity of lumasiran is demonstrated in animal models (mice, rats, monkeys) and in patients. In a typical efficacy study, lumasiran is administered subcutaneously (SC) to wild-type or HAO1-transgenic mice or to a rat model of PH1 (hydroxyproline loading model). Doses range from 0.3-10 mg/kg SC once monthly or less frequently. Liver tissue is harvested at various time points post-dose (e.g., days 1, 7, 14, 21, 28). HAO1 mRNA levels are measured by qRT-PCR, and glycolate oxidase enzymatic activity is measured in liver homogenates. The primary biomarker is plasma and urinary oxalate levels, which are measured using an enzymatic oxalate oxidase assay or LC-MS. Lumasiran treatment results in a dose-dependent reduction in HAO1 mRNA (>90% knockdown), reduction in GO activity (>90%), and a sustained reduction in urinary oxalate excretion. The duration of effect is several weeks, consistent with RNAi pharmacology.
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| ADME/Pharmacokinetics |
Lumasiran is a siRNA therapeutic with a distinct PK/PD profile. Following subcutaneous administration, it is absorbed into the systemic circulation and distributed primarily to the liver via GalNAc-ASGPR-mediated uptake. Plasma half-life is short (hours), but the pharmacodynamic effect on HAO1 mRNA lasts for weeks. In humans, after a subcutaneous dose of 3 mg/kg, the maximum plasma concentration (Cmax) is achieved in ~4 hours. The drug is cleared by endosomal degradation. The elimination half-life from the liver is approximately 10-20 days, supporting once-monthly or quarterly dosing. The major route of excretion is as nucleotides. The high liver:plasma ratio is a key feature of the GalNAc conjugate. No clinically significant drug-drug interactions are expected, as it is not a substrate or inhibitor of CYP450 enzymes.
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| Toxicity/Toxicokinetics |
In preclinical toxicology studies, lumasiran was well-tolerated. The primary findings in animals were expected on-target effects (reduced oxalate synthesis) and injection site reactions. No significant off-target effects were observed. The GalNAc conjugation has a high safety margin. In human clinical trials (Phase 3 ILLUMINATE studies), the most common adverse events were injection site reactions (e.g., erythema, pain) and nasopharyngitis. Serious adverse events related to the drug are rare. Lumasiran does not cause significant organ toxicity, hematologic abnormalities, or hepatic dysfunction. It is not genotoxic. Post-marketing surveillance continues to evaluate its long-term safety. As it is an RNAi drug, it is not metabolized by the liver, and therefore does not cause hepatotoxicity.
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| References | |
| Additional Infomation |
Lumasiran (Oxlumo®) was the first FDA-approved RNAi therapeutic for the treatment of primary hyperoxaluria type 1 (PH1), approved in November 2020. It is developed by Alnylam Pharmaceuticals. The drug is administered subcutaneously once every three months (quarterly) after an initial loading dose. Lumasiran is a 2'-O-methyl-modified, double-stranded siRNA conjugated to a triantennary GalNAc ligand. Its approval was based on results from the Phase 3 ILLUMINATE-A trial, which showed a 65% reduction in 24-hour urinary oxalate excretion. The CAS number is 1834610-13-7. For research use, it is provided as a solution or lyophilized powder. The molecular weight is approximately 16,763 g/mol (the WHO-10280 standard). Lumasiran is not for human use in research contexts; it is a prescription drug.
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| CAS # |
1834610-13-7
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| Appearance |
White to off-white solid powder
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
H2O : ~100 mg/mL
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| Solubility (In Vivo) |
Solubility in Formulation 1: 50 mg/mL (Infinity mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
(Please use freshly prepared in vivo formulations for optimal results.) |
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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