Marianne Farnebo | Linn Hjelmgren
Photo Credits
Ulf Sirborn | Sandro Schmidli
Scientific Frontline: Extended "At a Glance" Summary: Antisense Oligonucleotides (ASOs) and DNA Repair Disruption
The Core Concept: Antisense oligonucleotides (ASOs) are short, synthetic nucleic acid molecules utilized in gene therapies to regulate gene expression. Recent research indicates that these synthetic medicines can inadvertently disrupt the cellular systems responsible for detecting and repairing DNA damage.
Key Distinction/Mechanism: While natural DNA repair mechanisms activate in response to genuine structural damage, ASO molecules can bind directly to critical DNA repair enzymes and accumulate in dense nuclear clusters known as condensates or “PS bodies.” This binding falsely triggers a cellular repair signal even when no DNA damage exists, which can disrupt natural repair pathways and lead to an unsafe buildup of DNA alterations.
Major Frameworks/Components:
- Antisense Oligonucleotides (ASOs): Synthetic nucleic acid sequences formulated to target, bind to, and regulate specific messenger RNA (mRNA) or gene expressions.
- Nuclear Condensates ("PS bodies"): Dense, abnormal clusters formed within the cell nucleus when ASOs interact with DNA repair proteins.
- False DNA Damage Response: The incorrect cellular activation of repair signaling mechanisms in the absence of actual DNA degradation.
- Endogenous RNA Dynamics: Studying synthetic ASO behavior provides parallel insights into how natural RNA counterparts function within native DNA repair systems.
Branch of Science: Molecular Biology, Genetics, Biochemistry, and Pathology.
Future Application: The findings will drive advanced safety assessments for emerging genetic therapies and directly influence the molecular design and concentration dosing of future ASO-based drugs, ensuring they do not trigger unintended cellular stress responses.
Why It Matters: ASO therapies are already approved for clinical care and are heavily utilized in experimental treatments for genetic diseases. Understanding their potential to disrupt genomic stability at the molecular level is critical for minimizing clinical risks, refining drug safety profiles, and ensuring the long-term efficacy of synthetic gene medicines.
Antisense oligonucleotides (ASOs), used to treat genetic diseases, can affect how cells repair damage to their DNA. This is shown in a new study from Karolinska Institutet, published in the journal Nature Communications. The findings may have implications for the development of future genetic medicines and deepen our understanding of how RNA, natural counterparts to ASOs, participate in DNA repair systems.
ASO molecules are synthetic, short nucleic acid molecules used to regulate gene expression. They are included in several approved gene therapies and are being evaluated in many ongoing clinical trials. In the current study, researchers at Karolinska Institutet examined how these molecules influence the cellular systems responsible for detecting and repairing DNA damage.
The researchers discovered that ASO molecules can bind to some of the most important DNA repair enzymes in cells. When ASOs bind to these proteins, they accumulate in dense clusters in the cell nucleus, known as condensates or “PS bodies.” This also occurs at concentrations typically used in laboratory experiments.
Incorrect activation of DNA repair signals
The result is that the cell activates a repair signal even though there is no actual DNA damage, which may disrupt the natural repair process and lead to the buildup of harmful DNA alterations.
“Our results show that ASOs can trigger a repair response that should not normally be activated, and this could affect the cell’s normal handling of DNA damage,” says Marianne Farnebo, research group leader at the Department of Oncology-Pathology and the study’s senior author.
At the same time, she emphasizes that although the results may seem concerning, they must be put into context.
“It is important to distinguish between the ASO treatment we primarily studied and clinically used methods, where much lower concentrations of ASOs reach the cell nucleus.”
Important questions for the future of genetic medicines
The researchers stress that more and larger studies are needed to assess potential risks. But since ASO-based therapies are already used in clinical care, and many more are under development, the findings are already of importance. They may contribute to improved safety assessments and influence how future molecules are designed.
“Furthermore, our results show that the impact on DNA repair can occur in several distinct ways, not just through the clusters formed in the cell nucleus,” says Linn Hjelmgren, a doctoral student at the same department and the study’s first author.
The study is based on advanced biochemical analyses and microscopy, in which the researchers monitored how ASOs behave in cell models.
Published in journal: Nature Communications
Title: Dysregulation of the DNA damage response by phosphorothioate antisense oligonucleotides
Authors: Linn Hjelmgren, Qianyu Zhou, Sandro Schmidli, Manon Gloudemans, Tomasz Czapik, Samantha Roudi, Malgorzata Honcharenko, Daniel W. Hagey, Samir EL Andaloussi, and Marianne Farnebo
Source/Credit: Karolinska Institutet
Reference Number: mbio030326_01
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