By Michael McGinley, Senior Manager of Global Technical Support Department, Phenomenex
Oligonucleotides are a novel class of molecules that offer drug development researchers an enormous array of options in their search to treat a wide array of diseases. Equipped with the ability to bind to complementary sequences through Watson–Crick base pairing, they possess a unique potential to vastly improve the disease state for illnesses that have previously been considered untreatable. For example, oligonucleotides (also known as “oligos”) can target ribonucleic acid (RNA) molecules to treat genetic diseases or viral infections, folding upon themselves and binding to target molecules with incredible specificity.
Oligonucleotides are hardly new. For researchers and laboratory professionals—particularly those working in drug development and pharmaceuticals—oligos have long been a part of a potential toolkit of strategies that may have the potential to cure disease and improve patient outcomes. Synthetic oligonucleotides, in lab use for over 40 years, are now more common and are receiving regulatory approvals, notably in genetic diseases, anti-cancer treatments and metabolic disorders. So why now has this decades-old therapeutic begun to enjoy broader use? And what barriers persist to their widespread use?
One can cite many reasons for oligos’ slow adoption, including poor drug targeting and delivery, short in-vivo half-life, as well as moderate toxicity at the high doses required to see clinical efficacy. While challenges persist, improvements in drug formulation, stability, and potency are increasingly overcoming previous roadblocks for many disease indications.
Imagining what’s possible
More than a dozen oligonucleotide therapeutics have now received FDA approval, indicating a shift into mainstream use. Certainly, the record availability of COVID-19 mRNA vaccines in 2020-2021 underscores the value of oligos in vaccine development. As vaccine development shifts toward mRNA, given its relatively brief drug development timeline and relatively simple development process, oligos are poised to take a bigger role. And while still a way off, some research discussions have suggested trending toward using mRNA and gene therapy-based solutions rather than protein therapeutics.
The opportunity is hardly confined to vaccines. Some scientists are looking with renewed interest in oligo therapeutics as a path forward in addressing the more than 7,000 known rare diseases. It’s a thrilling proposition—and a life-changing one for patients and their families—that oligos have the potential to address, treat and even cure diseases previously considered difficult or impossible to drug.
One particularly exciting area of research is looking at combining antibody therapeutics with oligonucleotide therapeutics – attaching a piece of oligonucleotide onto a monoclonal antibody and delivering the antisense RNA into target cells. This approach may well be a new frontier in drug discovery, with oligo therapeutics taking the place of some of the recombinant therapies already available to patients.
Widespread use of oligos a lasting trend
There is a rapid expansion of oligonucleotide development underway, as researchers and pharmaceutical companies explore new platforms and methodologies for targeted delivery. Similarly, while past challenges with replicable, effective processes were the focus of just a few specialized oligonucleotide researchers, today most major pharmaceutical companies have been building their internal oligo expertise through hiring and other investments. This shift in interest from the pharmaceutical industry can be seen as a signal that we are only beginning to see the potential oligo therapeutics have in drug discovery and patient outcomes.
Protein therapeutics professionals, and in a few cases, small molecule pharmaceutical scientists, have also been a source of growing demand for oligonucleotide research capabilities. This shift, too, indicates that not only do pharmaceutical manufacturers see the business potential in oligo therapeutics, but that researchers who have worked for many years on rare and genetic diseases, for example, may be reinvigorated in their work as they move into oligos.
What is so difficult about oligo analysis?
But this brave new world is not without its challenges. In drug discovery and drug development, determining the pharmacodynamics and pharmacokinetics profiles can be difficult. Applications for oligonucleotide separations are a common request, allowing scientists to isolate and quantitate oligos from biological tissues and fluids. This is no easy task with oligos considering their chemical characteristics, yet isolation from other biological components is a critical step for subsequent analysis.
Oligonucleotides’ ability to directly interact with a cell’s protein synthesis machinery make them a powerful disease modifying agent, but they are also a target of nucleases that can rapidly break them down—thus negating their effect. Key in maintaining a therapeutic effect of an oligo drug is to use chemical modifications to slow down their breakdown by nucleases, thus increasing their half-life and their corresponding therapeutic effect.
Another foundational element to oligo development is the stability modifications and related obstacles in characterizing the oligonucleotides, their modifications, and their closely-related impurities. Indeed, purity can force researchers to rethink their approach. The inherent nature of oligos means that achieving 100% purity is not possible, confounding scientists who are used to protein purification and other therapeutics where a compound is more obviously “pure” or “not pure.” With oligos, we continue to learn where the quest for “perfect” becomes the enemy of “good.” This can be a mind-bender for some, and a place where analysis becomes stuck. An approach to oligo purity and activity needs a shift in thinking.
And finally, oligos don’t look like other drugs. The last few decades of oligo therapeutics research and discovery have seen oligonucleotide companies adjusting chemistries to achieve longer half-life, bioactivity and other characteristics. So, methodologies undertaken before may not be the foundation from which an oligo therapeutic is developed, modified, or analyzed today. Frustratingly perhaps, each time a chemistry change is made on an oligo, the methodology must be re-tested and potentially modified or changed.
It is clear from our work supporting this field that these novel challenges, paired with the rapid growth of the sector, are creating a need for tools and technologies that can properly define, analyze and test the drugs.
The partnership method: customized solutions
The rules for chromatography and separation are very different for oligonucleotides, holding back a field of discovery that has demonstrated enormous promise to humanity. Oligonucleotides’ ever-changing chemistry and the fact that they exist not quite fully within a biologist’s expertise, nor fully within a chemist’s, means advancing the field requires partnerships like never before.
Level-setting and education is the foundation of this partnership, helping researchers more deeply comprehend the unique approaches necessary to oligo methodology and analysis. And with each conversation, we work together to discern the right chromatographic solution, sometimes building out new methodologies together in the process. It’s exciting; pure collaboration at its finest, and it means our team can be part of a solution to industry challenges—even creating new molecules, if we need to! As a ‘hub’ for information and data-sharing alongside our customers, my team draws from a body of methodological knowledge, improving and expanding as we continue to tackle the unique questions and requests that come our way.
Ultimately, what makes oligos so challenging is the same thing that makes this expanding field so exciting: there is no single analytical solution. Collaborations, discussions, information-sharing and teamwork form the foundation of our partnerships with customers. And in the process of finding solutions, we inch forward toward a new, deeply satisfying era of understanding and treating disease.
References
- https://www.oligotherapeutics.org/the-emerging-era-of-n-of-1-drugs-for-ultra-rare-genetic-diseases/
About the Author: Michael McGinley is the director of applications at Phenomenex, leading a team that provides a scientific knowledgebase and technical support for life science products that are used across multiple market verticals: biopharmaceuticals, clinical testing, environmental and food analysis, biofuels, and specialty chemicals. He brings over 25 years of expertise in chromatography and biopharma drug development and frequently writes on analytical chemistry techniques and analysis.