Developing Oligonucleotide Therapies

Oligonucleotides are short strands of DNA or RNA molecules that contain a small number of nucleotides. Each nucleotide consists of a nitrogenous heterocyclic base (or nucleobase), a five-carbon pentose sugar (deoxyribose in DNA or ribose in RNA), and a phosphate group. The development of nucleotide and oligonucleotide therapeutics has been growing in importance over the past few decades. Cellular genomic blueprints are being targeted for treating diseases, as evidenced by the expanding number of FDA-approved nucleic acid medicines. These types of treatments can achieve long-lasting or even curative effects by inhibiting, replacing, or even altering genes. Most traditional medicines offer transient or temporary therapeutic results because they target proteins rather than the fundamental causes. Delivery strategies that improve stability, enable internalization, and boost target affinity are required for clinical translation and can potentially be achieved with oligonucleotide therapeutics.

What Are Oligonucleotide Therapeutics?

Oligonucleotide therapeutics are a novel class of drugs composed of short strings of synthetic nucleotides with high specificity and target molecules (such as mRNA or non-coding RNA) that cannot be controlled by conventional drugs. Oligonucleotide therapeutics are chemically synthesized drugs, the main skeleton of which is a chemically modified nucleotide. These nucleotide technologies make it possible to generate cutting-edge genetic medications, including tissue-specific nucleic acid bio-conjugates, mRNA, gene therapy, and gene-editing treatments. Importantly, nucleic acid delivery technologies are currently at the center of global efforts to combat the COVID-19 pandemic.

The History of Oligonucleotide Therapeutics

Friedmann and Roblin proposed nearly half a century ago that inherited genetic illnesses with malfunctioning genes could be cured by inserting a functional gene copy into a person’s DNA. The groundbreaking discovery of DNA as hereditary material in 1944, followed by an insightful study on DNA’s helical structure in 1945, set the path for our current understanding and utilization of nucleic acids, including the creation of oligonucleotide therapeutics. The history of oligonucleotide therapeutics is intertwined with that of basic molecular biology research and there are studies still going on today that are focused on important areas of nucleic acid research and therapeutics.

Types of Oligonucleotide Therapeutics and Delivery Platforms

The four, novel technological platforms which enable the clinical translation of nucleic acid treatments are:

  • antisense oligonucleotides (ASO)
  • ligand-modified small interfering RNA (siRNA) conjugates
  • lipid nanoparticles
  • adeno-associated virus vectors (AVV)

Exogenous nucleic acids are promising to provide highly focused, long-lasting, and perhaps curative therapeutic effects in both hereditary and acquired diseases by introducing them into cells to counteract defective genes. On the other hand, nucleic acids are difficult to use as treatments because they are prone to nuclease breakdown, contribute to immunological activation, and have unfavorable physicochemical properties that inhibit easy transfer into cells. As a result, advanced delivery platform technologies are required for safe and efficacious nucleic acid therapies. In previous decades, synthetic nucleosides or nucleotide analogues played a critical role in developing antiviral medications. However, these polar nucleoside medications were unable to cross cell membranes efficiently and interact with intracellular phosphorylases needed to convert them into active metabolites. As a result, these medications suffered from reduced therapeutic activity. To address these impediments, various lipophilic prodrugs were devised based on nucleoside mono-, di-, and triphosphates and implemented to efficiently deliver nucleosides into the target location while bypassing the rate-limited phosphorylation phase.

Antisense Oligonucleotides

Antisense oligonucleotides (ASOs) are single-stranded synthetic nucleic acid chains that target specific RNA transcripts through a variety of mechanisms. By breaking down the targeted transcript, inhibiting mRNA translation, or altering the maturation of the pre-mRNA via splicing correction, ASOs can reduce the amounts of mutant proteins. Chemical modification of ASO compounds has resulted in significant improvements in their pharmacological properties over time, making this class of medicines a great potential option for treating a number of neurodegenerative disorders. In recent years, ASO therapies have been used in the development of preclinical and clinical methods for various inherited neurodegenerative (polyQ) illnesses. The efficacy of ASOs in multiple animal models, and some remarkable results in the treatment of Huntington’s disease, lead to a bright future for ASO-based therapeutics for polyQ disorders in humans, providing novel strategies to fix unmet medical needs for this group of disorders.

How Oligonucleotide Therapies Work

Oligonucleotide therapies are chemically designed oligonucleotides that are complementary to specific mRNA. They are designed to enter cells or to be delivered into cells by lipid nanoparticles or adeno-associated viruses (AAV), halting the translation of a specific protein. Similarly, ASO medicines contain a critical component known as “noncoding mRNA,” which prevents a specific protein from being translated. According to their pharmacokinetic (PK) properties, oligonucleotides are widely dispersed in the liver, kidneys, fat cells, lymph nodes, spleen, and bone marrow. However, they are not able to be distributed into the brain. This is crucial for drug developers working on central nervous system (CNS) therapeutics since oligonucleotides are too big and negatively charged to penetrate the blood-brain barrier. Additionally, exo- and endo-nucleases play a role in oligonucleotide metabolism. Following that, the liver and kidneys typically excrete/remove them. In contrast to small molecule medications which are often taken orally, oligonucleotides are traditionally supplied subcutaneously or intravenously because they are typically large molecule medications. Recent research suggests that absorption enhancers, such as sodium caprate, might improve the intestinal permeability of oligonucleotides and make oral delivery easier, which would be beneficial to patients. Lastly, in regard to CNS therapies, oligonucleotides have generally required more intrusive ways of administration, such as an intrathecal injection, in which they are injected directly into the cerebrospinal fluid.

Advancements and Applications of Nucleotide Therapies

Over the last 30 years, groundbreaking research has helped develop safe and effective delivery vehicles for nucleic acid therapies. Several ex vivo and in vivo genetic medications for treating infections, cancer, muscular and retinal dystrophies, and other inherited illnesses have recently been approved (or are in late-stage development). For example, there have been a few approvals of chimeric antigen receptor T-cell (CAR T-cell) therapies in recent years. Several in vivo nucleic acid therapies have also received approval, such as chemical changes and/or technologies designed to preserve nucleic acids from degradation. Ensuring stability in the circulation, permitting localization to the target tissue, and providing adequate intracellular delivery are essential to the efficacy of these treatments. Chemically modified ASOs, N-acetyl galactosamine (GalNAc), ligand-modified siRNA conjugates, lipid nanoparticles (LNPs), and AAV vectors make up the vast majority of nucleic acid therapeutics that have been approved or are currently in late-stage clinical trials. These platform technologies are already paving the way for the next generation of nucleic acid medicines, including targeted nucleic acid conjugates, messenger RNA (mRNA), and gene-editing therapies.


Several techniques are emerging that contribute to transforming oligonucleotide therapies from an intriguing theory into clinical and practical reality. While currently, most approved nucleic acid treatments are designed to treat rare diseases, the delivery technologies for these types of therapies are now being used to generate more broadly applicable genetic medications and have also allowed rapid vaccine development in pandemic situations. Furthermore, these platforms help the clinical translation of innovative techniques like gene-editing medicines. Even though nucleic acid treatments confront several obstacles, including production, toxicity, and socioeconomic issues, it is evident that these therapies are poised to have a transformative influence on many diseases for which there were previously few or no therapy choices. Allucent understands the complexities behind developing nucleotide and oligonucleotide therapies. If you are developing an oligonucleotide therapy, contact us to learn more about how Allucent can help you make the most of your development program.

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