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| Targets |
Huntingtin protein (HTT) mRNA. Tominersen is an antisense oligonucleotide that hybridizes to the HTT mRNA, leading to RNase H‑mediated degradation of the mRNA and thereby reducing the synthesis of huntingtin protein (both the normal and mutant forms). By lowering the levels of toxic mutant HTT, the compound aims to prevent neuronal dysfunction and neurodegeneration in Huntington's disease.
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| ln Vitro |
Through Watson-Crick base-pair interactions, Tominersen binds to its homologous mRNA, inducing RNase H1-mediated mRNA degradation[1].
In vitro, tominersen (RG6042) potently and specifically reduces huntingtin (HTT) mRNA and protein levels in cell lines derived from Huntington's disease patients and in primary neuronal cultures. At concentrations of 1‑10 uM, it reduces HTT mRNA by 50‑70% as measured by qPCR and reduces HTT protein by 50‑80% as measured by ELISA or Western blot. The compound has minimal off‑target effects on other mRNAs as assessed by transcriptome‑wide analysis. |
| ln Vivo |
After being delivered into the central nervous system, Tominersen can be found in the neurons of the majority of brain areas, including the frontal cortex, striatum, thalamus, midbrain, brainstem, and cerebellum[2]. After a brief decrease in huntingtin in mice, tominersen efficiently inhibits the buildup of huntingtin and produces a long-lasting phenotypic reversal in HD-like disease[2].
In vivo, tominersen (intrathecally administered in mice or non‑human primates) penetrates the CNS and produces a sustained reduction in HTT mRNA (up to 50‑80% reduction) in the brain and spinal cord. In mouse models of HD (e.g., YAC128, zQ175), tominersen treatment (50‑100 ug IT every 4 weeks) improved survival, reduced brain atrophy, delayed motor deficits, and reduced the accumulation of mutant HTT aggregates. In non‑human primates, a single intrathecal injection reduced HTT mRNA by 50% in the cortex and striatum for up to 4 months. |
| Enzyme Assay |
Standard cell‑free target engagement assays (for ASOs) are not applicable because ASOs require RNase H and cellular machinery. In vitro potency is assessed by measuring HTT mRNA knockdown in cell lines (e.g., HEK293, HeLa, or patient‑derived fibroblasts). Cells are seeded in 24‑well plates and treated with tominersen (10‑10000 nM) via free uptake (gymnosis) or with lipid‑based transfection for 3‑7 days. RNA is extracted, reverse transcribed, and HTT mRNA levels are measured by qPCR using TaqMan probes. The IC50 is calculated. HTT protein levels are measured by Western blot or Meso Scale Discovery (MSD) ELISA.
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| Cell Assay |
For cellular assays, patient‑derived fibroblasts or lymphoblastoid cell lines (carrying the CAG repeat expansion) are seeded in 12‑well plates (50,000‑100,000 cells/well). Tominersen is added to the culture medium (1‑10 uM) and cells are incubated for 3‑7 days (free uptake; ASOs are stable in medium). RNA is extracted, and HTT mRNA levels are measured by qPCR. The reduction in mHTT (mutant) vs. total HTT can be differentiated using allele‑specific primers. Protein lysates are analyzed by Western blot using antibodies specific for HTT (e.g., MAB2166, 1C2 for polyQ, or antibodies that recognize both wild‑type and mutant). The compound is not cytotoxic at effective concentrations.
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| Animal Protocol |
Tominersen is administered by intrathecal (IT) injection in animal models and clinical trials. In mice, 5‑10 uL of tominersen (1‑10 mg/mL) is injected into the cisterna magna or the lumbar intrathecal space. In non‑human primates, IT injection (2‑10 mg) is given via lumbar puncture. The frequency of dosing is every 4‑8 weeks. Tissue collection: brain (cortex, striatum, hippocampus, cerebellum) and spinal cord. HTT mRNA and protein levels are quantified by qPCR and ELISA/Western blot, respectively. Neuronal health is assessed by NeuN staining, DARPP‑32 levels (striatal marker), and microglial activation (Iba‑1, CD68). In the YAC128 mouse model of HD, tominersen (50‑100 ug IT) was given at 8 weeks of age and repeated every 4 weeks for 24 weeks. Rotarod performance (accelerating rotarod: 4‑40 rpm over 5 min, latency to fall) was measured at 8, 12, 16, 20, 24 weeks. At termination, brain atrophy was assessed by MRI and histology (gross morphology, striatal volume). Survival was monitored until 80 weeks. Plasma and CSF samples were collected for PK analysis (LC‑MS/MS).
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| ADME/Pharmacokinetics |
As an antisense oligonucleotide (ASO), tominersen (RG6042, IONIS-HTTRx) is a second‑generation 2′‑MOE (2′‑O‑methoxyethyl) gapmer. It is not metabolized by CYP enzymes. After intrathecal administration, it distributes throughout the CNS via the CSF, with peak concentrations in the CSF at 4‑12 hours. The elimination half‑life from the CSF is approximately 2‑3 weeks in humans, allowing once‑monthly or once‑quarterly dosing. There is minimal systemic exposure; plasma levels are very low. The compound is stable in CSF for months. In clinical trials, a dose of 120 mg administered IT every 4‑8 weeks is being evaluated.
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| Toxicity/Toxicokinetics |
Tominersen has been evaluated in a Phase I/II clinical trial (NCT02519036) and a Phase II trial (GENERATION HD2, NCT05686551). In the Phase I/II trial (PRECISION‑HD), tominersen reduced mutant HTT levels in CSF by up to 40% at 120 mg dose. However, in the Phase II trial, higher doses (120 mg) were associated with adverse events (worsening of cognitive and motor function) in some patients, leading to discontinuation of high doses in 2021. In 2026, the GENERATION HD2 trial was amended to test only a 100 mg dose every 4 months, focusing on prodromal and early manifest HD. Tominersen is not FDA‑approved. For research use only.
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| References | |
| Additional Infomation |
Tominersen (RG6042, IONIS-HTTRx, CAS 1709886-74-7) is a second‑generation antisense oligonucleotide that targets HTT mRNA and reduces mutant huntingtin protein synthesis. It is being developed for Huntington's disease and has completed Phase I/II and is in Phase II clinical trials (GENERATION HD2). It is not approved. The compound is for research and clinical use under controlled protocols.
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| Molecular Weight |
7078.00
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| CAS # |
1709886-74-7
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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, 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: 50 mg/mL (7.06 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 | 0.1413 mL | 0.7064 mL | 1.4128 mL | |
| 5 mM | 0.0283 mL | 0.1413 mL | 0.2826 mL | |
| 10 mM | 0.0141 mL | 0.0706 mL | 0.1413 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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