Antisense Oligonucleotides

What are Antisense Oligonucleotides?

Antisense oligonucleotides are short, synthetic strands of nucleic acids that bind specifically to target RNA sequences. By attaching to RNA, they can model protein expression by blocking or altering RNA processing. They target diseases at the RNA level, addressing the root cause rather than just the symptoms. They remain a promising new method of treatment. Antisense oligonucleotides were discovered over two decades ago, but their development was slowed due to problems like weak biological activity and off-target effects. However, advances in chemical strategies have since improved their effectiveness. 

Benefits of Antisense Oligonucleotides

Antisense oligonucleotides offer several advantages over other therapies. They act directly on disease-causing RNA, allowing scientists to target the root cause of illness rather than just its effects. Their design is also highly flexible because they rely on predictable base-pairing, which makes it possible to develop antisense oligonucleotides quickly for a wide range of genetic targets. Chemical modifications have enhanced their stability and potency, while also reducing unwanted side effects. Compared to small-molecule drugs, antisense oligonucleotides often require less frequent dosing, sometimes only once every few months. Another major benefit is their potential for personalized medicine. For example, Milasen, a drug designed and developed in record time for a single patient, shows how antisense oligonucleotides can be tailored to an individual’s needs. Several antisense oligonucleotides, such as Nusinersen for spinal muscular atrophy and Eteplirsen for Duchenne muscular dystrophy, have already received FDA and EMA approval, proving their clinical success. 

Disadvantages of Antisense Oligonucleotides

Despite these benefits, antisense oligonucleotides face some challenges. One of the main issues is delivery, as they often accumulate in organs such as the kidney, liver, and spleen, which can cause toxicity. Although chemical improvements have reduced risks, antisense oligonucleotides can still bind to unintended sequences or even to themselves, leading to off-target effects. Another obstacle is scalability, since producing these therapies consistently at an industrial level is not simple. Current delivery systems also struggle to reach all the tissues that may need treatment. Finally, because many antisense oligonucleotides are designed for rare diseases or individual patients, the high costs of development can limit their accessibility. 

Uses of Antisense Therapy

Antisense oligonucleotides are being applied in a growing number of areas. They have already been approved for rare and genetic conditions such as spinal muscular atrophy, where Nusinersen has transformed treatment options, and Duchenne muscular dystrophy, where Eteplirsen and Golodirsen provide new hope for new patients. They are also used to treat hereditary transthyretin amyloidosis with drugs such as Patisiran and Inotersen. Beyond rare disorders, Inclisiran has been developed for cardiovascular conditions, showing the potential to benefit larger patient groups. Antisense oligonucleotides are especially promising in neurological diseases, many of which lack effective treatments. Researchers are also investigating their use in infectious diseases. For example, during the COVID-19 pandemic, antisense oligonucleotides were designed to target the viral genome, including genes for spike, membrane, and nucleocapsid proteins, as well as to modulate the immune system by suppressing cytokines or boosting protective interferons. 

Antisense Therapy Techniques

Several strategies are being employed to enhance the effectiveness of antisense oligonucleotide therapies. Chemical modifications are applied to improve stability, enhance binding to target RNA, and reduce toxicity. Antisense oligonucleotides can work in different ways, such as blocking protein translation, altering RNA splicing, or triggering the breakdown of RNA. Optimized delivery methods are also a major focus, with approaches like nanoparticle carriers or molecular conjugates helping to target specific tissues while avoiding harmful buildup in other organs. The field also has shown the power of precision medicine, with the rapid development of Milasen demonstrating how antisense oligonucleotides can be tailored for a single patient. In some cases, multiple antisense oligonucleotides are used to address the same disease, as seen with Duchenne muscular dystrophy, where different therapies expand treatment options depending on the patient’s specific condition.

References:

Rinaldi, C., & Wood, M. J. A. (2018). Antisense oligonucleotides: The next frontier for treatment of neurological disorders. Nature Reviews Neurology, 14(1), 9–21. https://doi.org/10.1038/nrneurol.2017.148 

Integrated DNA Technologies. (n.d.). Antisense oligonucleotides (ASOs). Retrieved [date you accessed], from https://www.idtdna.com/pages/products/functional-genomics/antisense-oligos

National Center for Advancing Translational Sciences. (n.d.). Antisense oligonucleotide (Glossary). In NCATS Discovery/Translation Glossary. Retrieved [date you accessed], from https://toolkit.ncats.nih.gov/glossary/antisense-oligonucleotide/

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