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| Targets |
AS‑Patisiran targets the transthyretin (TTR) messenger RNA (mRNA) in hepatocytes. The siRNA binds to the complementary sequence in TTR mRNA, leading to its cleavage by the RNA‑induced silencing complex (RISC) and preventing translation of the TTR protein. This reduces the production of both wild‑type and variant TTR monomers, which are the precursors of amyloid fibrils that deposit in peripheral nerves, heart and other tissues.
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| ln Vitro |
In cell‑free systems, AS‑Patisiran (like other siRNAs) does not have direct enzymatic activity. In cell‑based assays, the compound reduces TTR mRNA and protein levels in primary human hepatocytes and hepatoma cell lines (e.g., HepG2, Huh‑7). Treatment with AS‑Patisiran (1‑100 nM) for 24‑72 h leads to a dose‑dependent reduction in TTR mRNA, with an IC50 typically in the low nanomolar range. TTR protein secretion into the culture medium is also reduced, as measured by ELISA. The chemical modifications (e.g., 2'‑O‑methyl, 2'‑fluoro, phosphorothioate backbone) enhance stability and reduce off‑target effects.
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| ln Vivo |
In vivo, AS‑Patisiran has been extensively studied in rodent and non‑human primate models. In mice expressing human TTR, intravenous administration of AS‑Patisiran (0.1‑3 mg/kg) leads to a rapid and sustained dose‑dependent reduction in serum TTR protein levels, with maximal knockdown (>80%) achieved at 3‑7 days post‑dose. Knockdown is sustained for 3‑4 weeks after a single dose in rodents and for longer in primates (4‑8 weeks). In transgenic mouse models of hATTR amyloidosis, AS‑Patisiran reduces TTR deposition in peripheral tissues and improves nerve conduction velocity and other functional endpoints.
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| Enzyme Assay |
A standard in vitro TTR knockdown assay: Primary human hepatocytes or HepG2 cells are seeded in 96‑well plates (2×10⁴ cells/well) and cultured overnight. AS‑Patisiran is formulated with a transfection reagent (e.g., Lipofectamine 2000, RNAiMAX) according to the manufacturer's instructions. Cells are transfected with AS‑Patisiran (0.01‑100 nM) for 6 h, then the medium is replaced with fresh growth medium. At 24‑72 h post‑transfection, cells are lysed, and total RNA is extracted. TTR mRNA levels are quantified by RT‑qPCR using TTR‑specific primers, normalised to a housekeeping gene (e.g., GAPDH, beta‑actin).
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| Cell Assay |
TTR protein in the culture supernatant is measured by a human TTR ELISA. Percent knockdown is calculated relative to a non‑targeting control siRNA or mock‑transfected cells. IC50 values are derived from dose‑response curves.
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| Animal Protocol |
A standard in vivo TTR knockdown assay: Male hTTR transgenic mice (e.g., H1299 strain) or wild‑type mice are administered AS‑Patisiran intravenously via the tail vein at doses ranging from 0.03 to 3 mg/kg (n=5/group). Blood samples are collected pre‑dose and at various time points post‑dose (e.g., days 1, 3, 7, 14, 21, 28). Serum is separated, and TTR protein levels are quantified by a human‑specific TTR ELISA (for hTTR mice) or a species‑specific ELISA. Percent knockdown is calculated relative to pre‑dose or vehicle control levels. RNA is extracted from liver tissue at selected time points (e.g., day 7 post‑dose) to quantify TTR mRNA by RT‑qPCR. For tissue amyloid burden studies, transgenic mice are dosed weekly for 4‑8 weeks, and tissues (e.g., sciatic nerve, dorsal root ganglia, heart, gastrointestinal tract) are collected at necropsy for histopathological analysis (Congo red staining, Thioflavin S, or immunohistochemistry for TTR deposits).
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| ADME/Pharmacokinetics |
As a lipid nanoparticle‑formulated siRNA, AS‑Patisiran is administered intravenously. Following intravenous injection, the lipid nanoparticles (LNPs) are rapidly taken up by the liver via apolipoprotein E (ApoE)‑mediated endocytosis by hepatocytes. The siRNA is released from the endosome into the cytoplasm, where it loads into the RISC complex. The plasma half‑life of the LNP is short (minutes to hours), but the pharmacological effect (TTR knockdown) is sustained for weeks due to the stability of the siRNA and the slow turnover of the RISC complex. AS‑Patisiran has a low volume of distribution and is not extensively metabolised; the siRNA is cleared by renal excretion and nuclease degradation. The lipid components are metabolised and eliminated via standard lipid pathways.
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| Toxicity/Toxicokinetics |
In preclinical toxicology studies, AS‑Patisiran was generally well‑tolerated in rodents and non‑human primates at doses up to 10 mg/kg (weekly for 4 weeks). The most common adverse events observed in preclinical studies (and in clinical trials) are mild to moderate infusion‑related reactions (e.g., flushing, nausea, back pain, dyspnoea) and mild elevations in liver transaminases (ALT, AST). No significant hepatotoxicity or renal toxicity was observed at therapeutic doses. The compound is not genotoxic. The safety profile is consistent with lipid nanoparticle‑based siRNA therapeutics.
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| References |
[1]. Adams D, et, al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018 Jul 5;379(1):11-21.
[2]. Hoy SM. Patisiran: First Global Approval. Drugs. 2018 Oct;78(15):1625-1631. [3]. Kristen AV, et, al. Patisiran, an RNAi therapeutic for the treatment of hereditary transthyretin-mediated amyloidosis. Neurodegener Dis Manag. 2019 Feb;9(1):5-23. |
| Additional Infomation |
AS‑Patisiran is an investigational drug that has been approved (under the name patisiran, Onpattro™) for the treatment of hereditary transthyretin‑mediated amyloidosis (hATTR) in adults with polyneuropathy. Patisiran was the first siRNA therapeutic approved by the FDA (2018) and the first RNAi therapeutic approved for a genetic disease. The approved drug is formulated in a lipid nanoparticle (LNP) and is administered intravenously once every three weeks. AS‑Patisiran is the research grade form of the active pharmaceutical ingredient (API) of patisiran. Patisiran has demonstrated significant clinical benefit in patients with hATTR amyloidosis, including improved neuropathy scores, quality of life, and survival. For research use only; not for human therapeutic use outside of approved clinical indications. This compound is a powerful tool for studying TTR biology and developing RNAi‑based therapies for other amyloidogenic diseases.
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| Molecular Weight |
6661.30
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| Appearance |
Typically exists as solid at room temperature
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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, 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 (~15.01 mM)
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 0.1501 mL | 0.7506 mL | 1.5012 mL | |
| 5 mM | 0.0300 mL | 0.1501 mL | 0.3002 mL | |
| 10 mM | 0.0150 mL | 0.0751 mL | 0.1501 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
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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