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| Targets |
IONIS-MAPTRx targets the microtubule-associated protein tau (MAPT) mRNA, which encodes the tau protein. Tau is a microtubule-stabilizing protein that becomes hyperphosphorylated and aggregated into neurofibrillary tangles in Alzheimer‘s disease and other tauopathies. The antisense oligonucleotide binds to MAPT mRNA via Watson-Crick base-pair interactions, leading to RNase H-mediated degradation of the mRNA and subsequent reduction in tau protein synthesis. This tau-lowering approach aims to slow or halt the progression of tau pathology.
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| ln Vitro |
In vitro, IONIS-MAPTRx is evaluated in cell-based systems (e.g., human neuronal cell lines, iPSC-derived neurons) for its ability to reduce tau mRNA and tau protein levels. Treatment with the ASO leads to dose-dependent reduction of MAPT mRNA (measured by qPCR) and tau protein (measured by Western blot or ELISA). No specific IC50 or EC50 values are reported in the search results. The ASO is typically delivered by free uptake (gymnosis) in serum-containing medium or by using transfection reagents. Specificity is confirmed by measuring off-target effects on other transcripts.
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| ln Vivo |
In vivo, IONIS-MAPTRx has been evaluated in non-human primates and in a Phase 1 first-in-human clinical trial in patients with Alzheimer‘s disease. In non-human primates, the ASO reduced tau levels in the brain, spinal cord, and cerebrospinal fluid (CSF). The Phase 1 study (NCT03186989) evaluated safety, tolerability, and pharmacodynamics. The compound was administered intrathecally (IT) via lumbar puncture. Results are pending or have shown that the ASO is well-tolerated and reduces CSF tau levels. Preclinical efficacy in transgenic tauopathy mouse models (e.g., P301S mice) has also been demonstrated.
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| Enzyme Assay |
Binding of IONIS-MAPTRx to MAPT mRNA is measured by standard antisense oligonucleotide hybridization assays, including electrophoretic mobility shift assay (EMSA) or surface plasmon resonance (SPR) using a complementary RNA oligonucleotide representing the target sequence. The thermal stability (Tm) of the ASO-RNA duplex is assessed by UV melting curve analysis. Specific binding affinity (KD) is not reported. RNase H-mediated cleavage activity is confirmed in cell-free systems using a fluorescently labeled target RNA and recombinant RNase H.
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| Cell Assay |
For in vitro cellular assays, human neuronal cell lines (e.g., SH-SY5Y, Lund human mesencephalic (LUHMES) cells, or iPSC-derived cortical neurons) are seeded in 12- or 24-well plates. IONIS-MAPTRx is added at concentrations of 0.1-10 microM in serum-containing medium for 48-96 h (free uptake). Cells are then harvested, and MAPT mRNA is quantified by qPCR using TaqMan or SYBR Green assays. Tau protein levels are measured by Western blot (using antibodies such as Tau-5, HT7, or AT8 for phosphorylated tau) or by a sensitive ELISA (e.g., human tau ELISA kit). Cell viability is assessed by MTT or CellTiter-Glo assays.
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| Animal Protocol |
In vivo evaluation is performed in transgenic tauopathy mouse models (e.g., P301S, rTg4510, or hTau mice). IONIS-MAPTRx is administered intrathecally (IT) via lumbar puncture (single or repeated doses, typically 100-500 microg/injection) or intracerebroventricularly (ICV) via an implanted cannula. Dosing frequency is typically every 2-4 weeks for 3-6 months. At study endpoint, brains and spinal cords are collected. Tau mRNA is quantified by qPCR, and total tau and phosphorylated tau (e.g., AT8, AT180, PHF1) are quantified by Western blot, ELISA, or immunohistochemistry. Motor function is assessed by rotarod, grip strength, and open field tests. In non-human primates, CSF tau levels are measured as a pharmacodynamic biomarker.
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| ADME/Pharmacokinetics |
IONIS-MAPTRx sodium is a second-generation 2‘-O-(2-methoxyethyl) (2‘-MOE) modified antisense oligonucleotide with a phosphorothioate backbone for improved stability, reduced immunogenicity, and enhanced central nervous system (CNS) penetration. The molecular weight is approximately 7,000-8,000 Da. The ASO is water-soluble and formulated in saline for intrathecal administration. After IT administration, the ASO distributes throughout the CNS via the CSF circulation, with a CSF half-life of approximately 2-4 weeks in humans, enabling infrequent dosing (every 1-3 months). CSF concentrations correlate with brain tissue exposure. Systemic exposure is minimal following IT administration.
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| Toxicity/Toxicokinetics |
In Phase 1 clinical trials (NCT03186989), IONIS-MAPTRx was generally well-tolerated at doses up to 60 mg IT. The most common adverse events were post-lumbar puncture headache, back pain, and procedural pain. No dose-limiting toxicities or serious adverse events were reported. In preclinical studies, no significant neurotoxicity or systemic toxicity was observed at therapeutically relevant doses. No formal toxicology data (LD50, target organ toxicity) are provided in the search results. Long-term safety studies in animals have been completed to support clinical development.
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| References | |
| Additional Infomation |
IONIS-MAPTRx (BIIB080, diranersen sodium) is the first tau-lowering antisense oligonucleotide to enter clinical trials for Alzheimer‘s disease. It was developed by Ionis Pharmaceuticals in collaboration with Biogen. The compound targets the MAPT (microtubule-associated protein tau) mRNA and reduces tau synthesis. The Phase 1b study (NCT03186989) evaluated the safety and tolerability of multiple ascending doses of IONIS-MAPTRx in patients with mild Alzheimer‘s disease. Results from this study showed dose-dependent reduction of CSF tau levels and were presented at the 2019 and 2021 Alzheimer's Association International Conferences (AAIC). The compound is currently in Phase 2 clinical development (CELIA study) for Alzheimer‘s disease. IONIS-MAPTRx has the potential for treating other tauopathies including progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), and chronic traumatic encephalopathy (CTE). The compound is for research use only in its research grade and is not available for human use. IONIS-MAPTRx has not received regulatory approval. It represents a disease-modifying approach targeting tau pathology rather than amyloid plaques.
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| Molecular Weight |
7595.80
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| Appearance |
Solid powder
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| Synonyms |
BIIB080 sodium; ISIS 814907 sodium
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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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 | 0.1317 mL | 0.6583 mL | 1.3165 mL | |
| 5 mM | 0.0263 mL | 0.1317 mL | 0.2633 mL | |
| 10 mM | 0.0132 mL | 0.0658 mL | 0.1317 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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