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With the rise of nucleic acid therapeutics, antisense oligonucleotides (ASOs) have become a promising strategy for diseases beyond the reach of traditional drugs. ASOs modulate gene expression via RNase H-mediated mRNA degradation or splicing regulation, and advances in chemical modifications, delivery systems, and administration routes have improved their stability and pharmacokinetics. Over ten ASO drugs have been approved, with many more in trials, demonstrating their clinical potential.
Table 1. Approved ASO Therapies
| Generic Name | Type | Modification | Approval (Year/Region) | Target | RoA |
| Fomivirsen | ASO | PS | US 1998, EU 1999 | CMV IE2 mRNA | IVT |
| Mipomersen | ASO (gapmer) | PS, 2'-MOE | US 2013 | ApoB-100 mRNA | SC |
| Eteplirsen | ASO (SSO) | PMO | US 2016 | Dystrophin pre-mRNA | IV |
| Nusinersen | ASO (SSO) | PS, 2'-MOE | US 2016, EU 2017, JP 2017 | SMN2 pre-mRNA | IT |
| Inotersen | ASO (gapmer) | PS, 2'-MOE | US 2018, EU 2018 | TTR mRNA | SC |
| Volanesorsen | ASO (gapmer) | PS, 2'-MOE | EU 2019 | ApoCIII mRNA | SC |
| Golodirsen | ASO (SSO) | PMO | US 2019 | Dystrophin pre-mRNA | IV |
| Viltolarsen | ASO (SSO) | PMO | US 2020, JP 2020 | Dystrophin pre-mRNA | IV |
| Casimersen | ASO (SSO) | PMO | US 2021 | Dystrophin pre-mRNA | IV |
| Eplontersen | ASO (gapmer) | PS, 2'-MOE | US 2023 | TTR mRNA | GalNAc |
| Olezarsen | ASO (gapmer) | PS, 2'-MOE | US 2024 | ApoCIII mRNA | GalNAc |
| Imetelstat | ASO (gapmer) | PS, 2'-MOE | US 2024 | TERT mRNA | Naked |
| Donidalorsen | ASO (gapmer) | PS, 2'-MOE | US 2025 | SERPING1 mRNA | GalNAc |
Why In Vivo Studies Are Essential for ASOs
Although rational design and in vitro validation can identify promising ASO candidates, their performance in vivo often diverges due to nuclease degradation, limited cell uptake, or unanticipated toxicity. Comprehensive in vivo studies are indispensable for:
Creative Biogene provides a comprehensive in vivo evaluation platform for oligonucleotides, covering absorption, distribution, metabolism, and excretion (ADME), combined with pharmacodynamics (PD) and toxicokinetics (TK) assessments.
Creative Biogene offers a full suite of analytical technologies tailored for ASO quantification and metabolite profiling across diverse biological matrices (plasma, urine, tissue homogenates). By combining these complementary platforms, we ensure accurate, sensitive, and selective quantification throughout all PK phases.
| Method | Key Features | Applications |
| Hybridization-based ELISA (HELISA) | Highly sensitive (LOQ < 2 ng/mL), minimal matrix effect | Monitoring low plasma concentrations during the elimination phase (>24 h post-dose), measuring parent ASOs in plasma and urine |
| Non-competitive hybridization-ligation ELISA | Ultra-sensitive, selective for parent compounds, discriminates 3'-truncated metabolites | Accurate parent compound quantification with minimal cross-reactivity |
| HPLC + UV or MS/MS (Q-TOF-MS) | Robust separation and identification of full-length ASOs and metabolites | Early distribution phase, tissue and urine analysis |
| Ion-Pair Chromatography with MS (IPC-MS) | Balanced separation efficiency and sensitivity, a widely used LC-MS method | Standard ASO bioanalysis |
| Capillary Gel Electrophoresis | Size-based separation of intact ASOs and fragments | Characterization of ASO size and integrity |
Our in vivo PK services cover multiple administration routes, including intravenous, subcutaneous, intradermal, and intrathecal injection. Depending on ASO modifications (PS, PS-MOE, LNA, PMO, conjugated ASOs), we assess:
For CNS-targeted ASOs, our platform supports intrathecal PK profiling with prolonged tissue half-life (>100 days in spinal cord and brain).
To complement in vivo studies, Creative Biogene also offers in vitro metabolism assays using:
These models provide mechanistic insights into ASO degradation pathways (3'-exonuclease, 5'-exonuclease, endonuclease cleavage), predict metabolite profiles, and confirm enzyme stability of modified ASOs (e.g., 2'-O-MOE, 2'-O-Me, LNA, PMO).
Creative Biogene's ASO in vivo Testing Service combines scientific rigor with translational value. Key advantages include:
ASO therapy is rapidly reshaping the nucleic acid drug landscape. The complexity of ASO in vivo behavior requires systematic testing to ensure therapeutic success. Creative Biogene leverages advanced in vivo evaluation platforms, extensive nucleic acid drug expertise, and validated analytical methods to provide clients with end-to-end data support—from biodistribution and metabolism to PK/PD modeling. Our mission is to accelerate the transition of ASO candidates from the laboratory to clinical application by delivering reliable, translatable, and high-impact results. Partner with Creative Biogene, and gain a trusted collaborator in ASO in vivo testing.
Q1: How does in vivo ASO research differ from small molecule studies?
ASOs are primarily degraded by nucleases rather than CYP450 enzymes. Therefore, studies focus more on biodistribution, cellular uptake, and nuclease stability, especially in organs such as the liver and kidney.
Q2: Is radiolabeling necessary for biodistribution studies?
Radiolabeling is the gold standard, but technically challenging for oligonucleotides. We provide both radiolabeled and alternative fluorescence/mass spectrometry-based imaging approaches for high-resolution distribution analysis without radioactive risks.
Q3: How are dose and administration routes determined?
We recommend dose-escalation studies combined with PK/PD modeling that correlates plasma/tissue exposure with gene knockdown. Common administration routes include intravenous, subcutaneous, intrathecal, and local injections, depending on the target disease.
Q4: How do in vivo studies support clinical translation?
Cross-species metabolic and distribution comparisons help predict human pharmacokinetics, and our datasets allow benchmarking against existing ASO drugs, improving the accuracy of clinical dose projections.
Q5: How does Creative Biogene ensure data reliability?
Our studies follow GLP-like standards, with validated analytical methods, strict quality control, and reproducibility protocols to ensure international credibility.
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