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| Targets |
ubiquitin-protein ligase E3A (UBE3A)[1]
UBE3A (Ubiquitin-protein ligase E3A). Rugonersen is an antisense oligonucleotide (ASO) that targets the UBE3A-AS (antisense transcript). By binding to the UBE3A-AS transcript, it prevents the silencing of the paternal UBE3A allele in neurons, leading to increased UBE3A protein expression from the functional paternal copy. |
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| ln Vitro |
In neurons from Angelman syndrome (AS), RO7248824 (0-10 μM) exhibits nanomolar potency against UBE3A-ATS (EC50=26.3 nM), UBE3A mRNA upregulation (EC50=15.4 nM), and UBE3A protein upregulation (EC50=24.8 nM)[1].
In vitro, Rugonersen, an LNA-modified ASO, reduces the expression of the UBE3A antisense transcript, which normally silences the paternal UBE3A allele. By reducing the level of this antisense RNA, it enables the transcription and translation of the functional paternal UBE3A gene, leading to the production of UBE3A protein in neuronal cells. In cells derived from Angelman syndrome patients, treatment with Rugonersen restores UBE3A protein levels. |
| ln Vivo |
Rugonersen (RO7248824) (24 mg/monkey; it; for 8-85 d) induced a strong, long-lasting (up to 3 months) paternal reactivation of UBE3A mRNA/protein across important monkey brain areas, and it is well tolerated without causing tissue pathology or harmful in-life effects[1]. Rugonersen (150 μg; icv; single dosage) specifically and potently decreases UBE3A-ATS in male cynomolgus monkeys[1] while simultaneously upregulating UBE3A mRNA and protein[1].
In vivo, Rugonersen has been studied in mouse models of Angelman syndrome. Administration directly into the central nervous system (e.g., intracerebroventricular injection) leads to an increase in UBE3A protein levels in the brain and ameliorates the neurological deficits associated with the disease, such as motor dysfunction and cognitive impairments. These data support its potential as a disease-modifying therapy for Angelman syndrome. |
| Enzyme Assay |
Rugonersen is an ASO, not a small molecule, and its activity is not typically evaluated in standard cell-free enzyme assays. Instead, its target engagement is assessed by measuring the levels of its target RNA. The ASO is incubated with RNA extracted from cells or tissues in a cell-free system, and the interaction is confirmed by Northern blot or RT-qPCR. More commonly, its activity is evaluated directly in cellular systems.
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| Cell Assay |
For cellular assays, neurons derived from patients with Angelman syndrome or mouse models are treated with Rugonersen (typically 1-10 uM) for 24-72 hours. The cells are harvested, and UBE3A mRNA levels are measured by RT-qPCR, and UBE3A protein levels are measured by Western blot and immunofluorescence. The reduction of the UBE3A antisense transcript is also confirmed by RT-qPCR. The IC50 for increasing UBE3A expression is determined.
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| Animal Protocol |
Animal/Disease Models: Male cynomolgus monkey[1]
Doses: 24 mg per monkey Route of Administration: Intrathecal injection; single dose or twice dose with 2 weeks apart; sacrificed at 8, 15, 29, 57, and 85 days after the last dose Experimental Results: Resulted a long duration of action on paternal UBE3A reactivation in NHP brains after IT delivery. Animal/Disease Models: WT and AS Ube3a m-/p+ mice adult mice (10-12 weeks old)[1] Doses: 150 μg per mice Route of Administration: Intracerebroventricular injection; single dose; harvested at 2 weeks post injection Experimental Results: Revealed a steep relationship between UBE3A-ATS knock-down and UBE3A mRNA/protein upregulation, whereby an almost 90% downregulation was needed to achieve a 50% upregulation, respectively. For in vivo studies, Rugonersen is administered by intracerebroventricular (ICV) injection or intrathecal (IT) injection into the central nervous system of mouse models of Angelman syndrome (e.g., Ube3a maternal knockout mice). Doses range from 10-200 ug per injection. Tissues (e.g., hippocampus, cortex, cerebellum) are harvested at various time points (e.g., day 7, day 28). UBE3A protein levels are measured by Western blot and immunohistochemistry. Behavioral testing (e.g., open field, rotarod, novel object recognition) is performed to assess motor function, learning, and memory. ASO distribution in the brain is assessed by in situ hybridization. |
| ADME/Pharmacokinetics |
Rugonersen, being an ASO, has a distinct pharmacokinetic profile when administered intrathecally. It distributes widely throughout the central nervous system (CNS) and is taken up by neurons and glial cells. The half-life in the CNS is long (weeks to months), allowing for infrequent dosing. Systemic exposure following IT injection is low. Detailed PK parameters (Cmax, AUC, elimination half-life) are determined in preclinical studies by measuring ASO levels in plasma and CNS tissue using a hybridization-based ELISA or LC-MS/MS.
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| Toxicity/Toxicokinetics |
Toxicological data for Rugonersen are derived from preclinical toxicology studies. These studies typically involve IT administration to rats and non-human primates. Observed toxicities may include inflammation at the injection site (in the cerebrospinal fluid or spinal cord), as well as dorsal root ganglion (DRG) toxicity or peripheral neuropathy, which are class effects for ASOs. The therapeutic index is established by comparing the efficacious dose with the no-observed-adverse-effect level (NOAEL).
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| References | |
| Additional Infomation |
Rugonersen is an investigational drug candidate that was in clinical development for the treatment of Angelman syndrome. It was developed by Roche and is also known as RG6091 and RO7248824. As of 2023, clinical trials were discontinued. The compound is for research use only and is not approved by the FDA. Angelman syndrome is a rare neurogenetic disorder characterized by intellectual disability, developmental delay, severe speech impairment, and ataxia.
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| CAS # |
2591587-57-2
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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: ≥ 100 mg/mL (15.31 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.) |
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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