In fact, since the emergence of these complex molecular technologies, ASOs have paved the way for new personalized medicines and tailored treatments, helping scientists address the underlying genetic factors responsible for someone’s illness. Below, we take a closer look at what ASOs are, and how we can expect them to change the world of modern medicine over the next decade.

What are antisense oligonucleotides and how do they work? 

Antisense oligonucleotides are short, single strands of synthetic DNA, designed to regulate gene expression. They are made through a complex process of chemical synthesis, whereby the four nitrogenous bases of adenine (A), cytosine (C), guanine (G) and thymine (T) are joined together in specific sequence to form a chain of 8-50 nucleotides. This then presents the structural base of DNA which contains an organism’s genetic code. 

When these are administered to a patient to treat a genetic disorder, ASOs can be designed to target almost any RNA sequence. According to the PHG Foundation, this can be done in two different ways:

Degradation: Also known as gene silencing, ASOs bind to and promote the degradation of faulty mRNA by enzymes within cells, stopping gene expression. 

Steric blockage: Binding to target pre-mRNA or mRNA and interrupting the interactions with proteins involved in splicing or translation. This modulation of splicing results in the selective inclusion or exclusion of exons or introns from the pre-mRNA that make up a functional mRNA.

According to biobide, this innovative approach holds significant potential as a therapeutic solution for a wide range of conditions, including cancer, neurodegenerative disorders, genetic diseases and viral infections.

What are antisense oligonucleotides used for?

Since their emergence, ASOs have already produced great results in the treatment of rare neurological disorders such as spinal muscular atrophy (SMA) and Duchenne muscular dystrophy (DMD). According to the U.S. National Library of Medicine, there are also 122 registered clinical trials for the treatment of diseases such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), cancer, cystic fibrosis, Parkinson’s disease and rheumatoid arthritis.

However, according to Pharmaceutical Outsourcing, ASOs can have mild-to-moderate toxic effects, such as thrombocytopenia, elevated liver enzymes and hyperglycemia. That said, the side effects are much more controllable than in other classes of drugs. In fact, more recently, scientists have created fourth-generation ASOs, which boast improved stability of the treatment through reduced toxicity and improved drug delivery. 

In addition, the treatments of ASOs are much better suited for personalized medicine, as their chemical base can be altered to target specific diseases and genetic profiles, according to Nature Reviews Drug Discovery.

ASOs have great difficulty penetrating the cellular membrane, leading to suboptimal tissue absorption. As a result, they are frequently administered via lumbar puncture to target the central nervous system (CNS). This makes them highly effective at treating DMD, familial amyloid polyneuropathy and hereditary transthyretin amyloidosis. 

But in recent research, new methods, such as topical applications and enema preparations, are also showing promising outcomes. 

What are some examples of antisense oligonucleotides?

Several antisense oligonucleotides have been approved for clinical use, including:

• Nusinersen (marketed as Spinraza ®): used to treat spinal muscular atrophy (SMA).
• Eteplirsen (Exondys 51 ®): developed for Duchenne muscular dystrophy (DMD).
• Inotersen (Tegsedi®): approved for hereditary transthyretin-mediated amyloidosis.

These ASOs work by modulating RNA to either silence harmful gene expression or correct faulty splicing, representing a major breakthrough in precision medicine and targeted treatment of rare genetic diseases.

What are the benefits of antisense oligonucleotides?

ASOs hold great promise in the future of modern medicine, capable of addressing the root cause of many genetic diseases. This potential extends to a wide spectrum of conditions, including genetic disorders, neurodegenerative diseases and certain cancers.

Understanding the way in which ASOs can interrupt specific interactions with proteins, biomedics can create personalised medicines that match an individual’s unique genetic profile. Better yet, ASOs are generally well-tolerated by the immune system, reducing the likelihood of adverse reactions.

These molecules are also very versatile in their administration, with options including intravenous, subcutaneous, topical or enema delivery, making them adaptable to diverse medical scenarios. 

And their therapeutical applications are still evolving, with scientists using ASOs to treat rare infectious diseases such as hepatitis B virus (HBV) and SARS-CoV-2. According to Pharmaceutical Outsourcing, other RNA technologies in development are treatments for cystic fibrosis, haemophilia A, retinitis pigmentosa and frontotemporal dementia with parkinsonism. 

What are the challenges of ASO therapies?

According to the PHG Foundation, ASO therapies, despite their promising future, come up against several significant challenges. First and foremost, the delivery to specific tissues can be complex, particularly when targeting the central nervous system (CNS). Because of this, patients will have to receive much more invasive methods of administration, like a lumbar puncture. 

ASOs can also undergo chemical modifications, but this approach can increase the risk of toxicity or provoke an inflammatory immune response. There are also concerns related to on-target and off-target effects. On-target effects refer to unintended consequences stemming from the alteration of gene expression in the target RNA, while off-target effects occur when the ASO’s sequence lacks specificity, impacting multiple genes instead of just the intended target.

Additionally, ASOs do not always offer a cure, although they may slow down the disease, or simply just improve symptoms. Subsequently, this makes it hard to determine their efficacy, especially when a patient has been diagnosed with the disease after showing symptoms. It also makes it hard to create personalized medicines due to the uncertain disease trajectory. 

Finally, scientists are still questioning the role of ASOs when it comes to drug interactions. For instance, can a patient receive ASOs and chemotherapy together to treat their cancer diagnosis? 

Despite these challenges, ASOs hold great promise of enhancing the quality of life for millions of people who are otherwise suffering from incurable genetic disorders. Some of these treatment options have now been accepted by the FDA and EMA, and this is just the start of revolutionizing modern medicine. 

Looking for a convenient tool to determine oligonucleotide molecular weight? Try our helpful oligonucleotide calculator today.