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Home NEWS Science News Health

Profiling Antibodies Targeting Chemical Modifications in Antisense Oligonucleotides

Bioengineer by Bioengineer
July 31, 2025
in Health
Reading Time: 4 mins read
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In a remarkable advancement within the field of nucleic acid therapeutics, researchers have unveiled a new set of antibody tools capable of precisely targeting chemically modified antisense oligonucleotides (ASOs). These innovations promise to revolutionize how scientists track and understand the intracellular trafficking and biodistribution of ASO therapeutics, enabling a deeper understanding of their mechanisms and optimizing their delivery in vivo. Published in the esteemed peer-reviewed journal Nucleic Acid Therapeutics, the study represents a significant leap forward in preclinical evaluation and therapeutic development of nucleic acid-based drugs.

ASOs are synthetic strands of nucleic acids engineered to selectively bind to specific RNA sequences, modulating gene expression with therapeutic intent. Recent advances have introduced chemical modifications such as phosphorothioate backbones and 2′-O-methoxyethyl (2’-MOE) groups to enhance stability, cellular uptake, and affinity. However, these modifications have complicated researchers’ ability to track ASOs precisely within cells and whole organisms, hindering the development pipeline of these therapeutics. Addressing this challenge, scientists led by Peter Oliver and Xiao Wan from the Research Complex at Harwell in the U.K. have developed and validated new antibodies that specifically recognize these modifications with high fidelity.

The research team utilized a combination of immunocytochemistry and immunohistochemistry to confirm that their novel antibodies could selectively bind to the phosphorothioate and 2′-MOE modifications across multiple biological contexts. In vitro experiments demonstrated clear visualization of intracellular ASO localization within cultured cells, while in vivo studies in murine models delineated tissue-level biodistribution. This dual approach is invaluable because it offers insights into both cellular trafficking pathways and whole-body kinetics of oligonucleotide therapeutics, which are essential for optimizing dosing strategies and reducing off-target effects.

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Such detection capabilities are crucial due to the complex nature of ASO distribution. After systemic administration, ASOs must navigate through serum proteins, cross biological barriers, and reach target tissues without degradation. The phosphorothioate modification, replacing a non-bridging oxygen with sulfur in the backbone, confers nuclease resistance and influences protein binding, yet complicates antibody recognition. The 2′-MOE modification further enhances affinity and metabolic stability but has similarly posed unique challenges for characterizing biodistribution. These new antibodies resolve these issues by binding to the chemical moieties themselves rather than the nucleotide sequence, enabling universal application across diverse ASO sequences.

One important implication of this technology is the facilitation of quantitative immunoassays and preclinical workflows. By detecting chemically modified ASOs irrespective of their sequence, these antibodies can standardize and expedite the screening of oligonucleotide candidates during drug development. Researchers no longer need to develop sequence-specific probes or rely on indirect methods such as radiolabeling, which can be cumbersome and non-specific. Instead, direct immunodetection enhances reproducibility and sensitivity, enabling rapid data acquisition across both cell types and animal models.

The findings underscore how improved molecular tools can drive forward the burgeoning field of nucleic acid therapeutics (NAT), which seeks to harness RNA-targeting and gene expression modulation for treating genetic disorders, cancers, and infectious diseases. Nucleic acid therapies are uniquely positioned to target “undruggable” proteins and pathways, but their clinical success depends heavily on effective delivery and action at precise cellular locales. Thus, the ability to visually track ASOs advances not only fundamental pharmacokinetic studies but also informs rational design of next-generation modalities.

Executive Editor Graham C. Parker, PhD, from Wayne State University’s Carman and Ann Adams Department of Pediatrics, emphasizes the importance of these antibodies in streamlining preclinical translation. He articulates that advancing expedited therapeutic development requires better tools to robustly trace oligonucleotide behavior in vivo. The availability of reagents recognizing backbone and sugar modifications transforms this landscape, heralding a new era where delivery hurdles can be systematically addressed and overcome through precise visualization.

The broader implications for clinical application are immense. Antisense oligonucleotides with phosphorothioate and 2′-MOE modifications are already prominent in FDA-approved drugs treating conditions like spinal muscular atrophy and Duchenne muscular dystrophy. The ability to quantify their biodistribution using these antibodies informs both safety and efficacy assessments, reducing risks of adverse effects stemming from off-target accumulation. Moreover, new therapeutic constructs incorporating these chemical features can now be swiftly evaluated in animal models, accelerating their path to clinical trial readiness.

Published bimonthly, Nucleic Acid Therapeutics serves as the authoritative journal for this fast-evolving domain, disseminating groundbreaking research on manipulating gene expression via novel nucleic acid chemistries. Under the editorial leadership of renowned experts Bruce A. Sullenger, PhD, and Annemieke Aartsma-Rus, PhD, the journal highlights innovations spanning from molecular biology to translational therapeutics. This article solidifies its standing as a crucial resource for bridging basic research with clinical innovation in oligonucleotide therapeutics.

The Oligonucleotide Therapeutics Society, a non-profit consortium fostering collaboration across academic and industrial researchers, endorses this research as a pivotal contribution to the field. Its mission to unlock the full potential of oligonucleotides for therapeutic use is exemplified through such advancements that harmonize cutting-edge chemistry with practical biomedical application. Collaborative societies and journals continue to propel nucleic acid science into new therapeutic frontiers with tools like these antibodies.

In conclusion, this study not only tackles a fundamental challenge in ASO therapeutic development—tracking chemically modified oligonucleotides with sequence-independent antibodies—but also establishes a platform to accelerate drug discovery and refine our mechanistic understanding of nucleic acid delivery. By enhancing our capacity to visualize ASOs in complex biological systems, these new antibodies mark a turning point, offering a critical means to propel antisense therapeutics from bench to bedside with increased precision and confidence.

Subject of Research: Animals

Article Title: Characterizing Antibodies Targeting Antisense Oligonucleotide Phosphorothioate and 2′-O-Methoxyethyl Modifications for Intracellular Trafficking and Biodistribution Studies

News Publication Date: 21-Jul-2025

Web References:

https://www.liebertpub.com/doi/10.1177/21593337251361396
http://www.liebertpub.com/nat

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References:
Oliver P., Wan X., et al. (2025). Characterizing Antibodies Targeting Antisense Oligonucleotide Phosphorothioate and 2′-O-Methoxyethyl Modifications for Intracellular Trafficking and Biodistribution Studies. Nucleic Acid Therapeutics. DOI: 10.1177/21593337251361396

Image Credits: Mary Ann Liebert, Inc.

Keywords:
Molecular biology, Biomolecules, Adenosine diphosphate, Base pairs, DNA, Nucleobases, Nucleic acids, Oligonucleotides, Polynucleotides, Guanine nucleotides, Adenine nucleotides, Nucleotides, RNA, Drug delivery, Drug therapy, Medications, Pharmacology, Routes of administration, Drug delivery systems, Dose response curve, Drug combinations, Drug dosage, Drug safety, Drug targets

Tags: 2′-O-methoxyethyl groups in RNA therapeuticsantibodies targeting modified antisense oligonucleotidesbiodistribution of ASO therapeuticschemical modifications in nucleic acid therapeuticsimmunocytochemistry in nucleic acid researchintracellular trafficking of antisense oligonucleotidesphosphorothioate backbones in ASOspreclinical evaluation of nucleic acid drugstherapeutic development of ASOstracking chemically modified oligonucleotides

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