Awakening the Giant: The Next Frontier in mRNA Therapeutics

The remarkable success of messenger RNA-based vaccines during the COVID-19 pandemic has sparked widespread interest and enthusiasm around mRNA technology. But vaccines are just the beginning. Researchers and biotech innovators worldwide are rapidly uncovering the broader potential of mRNA to address a vast array of health challenges, from cancer and genetic diseases to regenerative and cell therapies.

In this article, we explore the exciting trends, promising advancements, and real-world challenges shaping the future of mRNA therapeutics. We’ll take a closer look at the groundbreaking science, the critical regulatory considerations, and the practical hurdles that must be overcome for mRNA-based treatments to become commonplace. We will examine what’s next for mRNA and how this powerful technology could transform medicine and improve countless lives.

Despite fewer front-page headlines in recent times, mRNA is poised to transform the landscape of therapeutics and vaccines.

Not so long ago, it was hard to go a day without hearing one breathtaking report after another describing the revolutionary possibilities of mRNA. In the tense and deadly days of the COVID-19 pandemic, while the world was waiting and the biopharma industry worked tirelessly, mRNA vaccines were developed and rolled out at an unprecedented pace.

Given the ebb and flow of headlines and promises around mRNA medicines, all it’s easy to ask, “Is mRNA just a flash in the pan?” The simple answer is “no”. With the advent of even more mRNA vaccines and therapeutics hitting the market, the global mRNA therapeutics market size is growing at a brisk 17.05% compounded annual growth rate and, by 2030, is projected to reach $32.5 billion¹ in annual global revenue. While infectious disease vaccines are expected to retain a dominant position within the mRNA sector, oncology, respiratory diseases, autoimmunity, and rare genetic diseases, among other disease states, are gaining footholds in preclinical and clinical development and will make up an increasing share of the market in the upcoming years. However, questions remain – why is mRNA so well-positioned, and what challenges must be overcome?

As a therapeutic class, mRNA shines in numerous key aspects, including rapid and flexible development, scalable and efficient manufacturing, patient safety, therapeutic efficacy, and regulatory momentum. As a gene transfer technology, mRNA allows for the transient expression of transgenes, large and small. Because mRNA is delivered non-virally, it can be re-dosed to achieve the desired clinical effects.

Rapid and Flexible Development – mRNA is a novel drug platform technology that provides the cells of the body “instructions” to make virtually any protein, native or synthetic. With the genetic sequences of a desired protein or antigen in hand, medicinal mRNA is synthesized in vitro, without the cell culture and a heavy purification burden. Medicinal mRNA can be developed quickly because regardless of the clinical application, the manufacturing process and controls for mRNA have been standardized. Its therapeutic flexibility is rooted in to encode any protein needed for in situ expression.

Agile Therapeutic Iteration – Once the genetic code for a target protein is known, mRNA molecules can be quickly designed and synthesized. This allows developers to prototype and refine therapeutic candidates rapidly.

Scalable and Cost-Effective Manufacturing – Because mRNA is produced through a cell-free, enzymatic process, it is simple to scale up.. The manufacturing process is not reliant on variable biological systems that require time-consuming, finicky cell culture.

Patient Safety – mRNA is expressed transiently and does not integrate into the host genome. This reduces the risk of insertional mutagenesis, a significant patient safety concern for some gene therapies. mRNA’s transient nature also means that protein expression duration and intensity can be tightly controlled, which has become a very useful feature for gene editing applications. Additionally, with proper chemical modifications and optimized non-viral delivery systems, mRNA medicines have low undesirable immune responses while still eliciting the desired therapeutic effect.

Regulatory Experience – The COVID-19 pandemic resulted in an emergency state proof-of-concept. While global regulators are working to create guidelines now that the state of emergency has passed, they have experience with these drug products that will improve access to mRNA medicines as they increasingly make their way through the development pipeline.

Despite the significant business risk of vaccine development and manufacturing, it has been a key sector with a healthy development pipeline and solid revenue growth. However, the market slowed in the early 2000s, and by 2019, the global vaccine pipeline was struggling, and revenue growth was anemic.² Without government support, vaccines present a challenging commercial story. They tend to require high capital investment, endure long regulatory approval timelines, can be difficult to manufacture, and have unpredictable demand.

However, in the first 20 months of the COVID-19 pandemic alone, governments worldwide invested more than $100 billion in vaccine development and manufacturing.³ While this level of aggressive spending eased as the emergency status of the pandemic waned, the business case for vaccine development has been strengthened. For example, Pfizer and BioNTech continue building an mRNA vaccine pipeline. While there have been stumbling blocks, the duo is making progress developing mRNA-based influenza vaccines and combination COVID-influenza vaccines.⁴ This said, it seems likely that Moderna’s COVID-19-influenza combination vaccine could be the first to market.⁵

In October 2024, the FDA approved Moderna’s RSV vaccine, mRESVIA^®, for the prevention of severe outcomes in older adults.⁶ Yet, Moderna is continuing to advance its pipeline – phase III trials of its mRNA-1647 for cytomegalovirus (CMV), the most common infectious disease-related cause of birth defects in the U.S, are underway.⁸

mRNA is advancing well beyond infectious disease prevention, and pursuing treatment for numerous cancers is at the forefront. Tumor-specific antigens and immune-stimulating molecules in cancer vaccines work to stimulate the patient’s immune system to target and eliminate cancer cells with tumor-associated antigens (TAAs), or other mechanisms.

Additionally, mRNA shows promise in gene and cell therapy by providing instructions on how to replace or supplement disease genes and proteins. While in pre-clinical stages, one study demonstrated the delivery of factor IX encoding mRNA for treating hemophilia B in a mouse model. Another showed promise in developing an mRNA therapy in mice to treat methylmalonic acidemia. Yet other studies are exploring the use of mRNA to encode the vascular endothelial growth factor A gene for cardiac tissue repair in cases of heart attack.

Also, due to the ability to quickly manufacture mRNA with altered genetic instructions, mRNA is poised to support the development of personalized gene therapies and cancer vaccines. Utilizing mRNA in this manner, patients’ genotypic characteristics could be used to develop patient-specific cures for genetic disease and cancer or to address a wide variety of other disease states.

Gene therapy’s strength is the ability to cure patients by correcting genetic defects, and viral vectors have reigned supreme as genetic material delivery systems. But, viral vectors present considerable drawbacks such as strong immunogenicity, genomic integration risks, and difficulty regulating gene expression. Additionally, adeno associated virus (AAV) vectors, the leading viral vector technology, are complex and costly to manufacture.

However, mRNA offers a promising alternative as it can restore missing or defective proteins by transient expression without changing genomic sequences. This approach corrects the genetic issue while avoiding viral-vector safety concerns and limitations on the size of the transgene.

mRNA can also be exploited for gene editing. For example, mRNA can be used to encode Cas9 or other gene editing proteins that can be delivered to target cells for potent, transient expression of the gene editing protein. mRNA is preferred over viral-vectors for this application to reduce off-target effects, risks of insertional mutagenesis, and to allow for larger gene editing proteins to be used.

While mRNA shows much promise, there are challenges stakeholders across the industry are working to address. For one, in vitro transcription (IVT), the foundation of mRNA synthesis, faces several efficiency-related issues. Clinical and commercial demands require high-yield production, but enzyme inefficiencies and template design can limit output. Additionally, IVT often produces incomplete or aberrant transcripts, as well as by-products that must be removed to achieve the needed product quality. Finally, scaling an IVT process without negatively impacting quality remains a meaningful complication.

Capping efficiency and mRNA stability present another series of challenges. For mRNA to be biologically active and stable, a 5′ cap structure is required. However, co-transcriptional and enzymatic capping processes can be inefficient, leading to incomplete capping.

While incomplete capping impacts processing efficiency, it can also negatively impact patients. Even though mRNA tends to fare much better than viral-vectors from a risk of immunogenicity standpoint, uncapped mRNA is rapidly degraded, can trigger immune responses, and reduce therapeutic efficacy.

Purification, another critical part of the mRNA production process, is required to remove impurities such as enzymes, DNA templates, and unwanted transcripts. But, many chromatography methods are challenged to balance high yield with the ultra-high purity essential for clinical applications. While managing impurities is critical for virtually any therapeutic product, mRNA impurities are particularly problematic as they can trigger adverse patient immune responses.

The largest ever commercial application of mRNA was, of course, the COVID-19 vaccines–an effort pursued under emergency conditions that could not wait for regulations to be fine-tuned. Instead, regulatory thought processes were basically developed in real-time with the industry and leading global regulatory bodies working hand in hand.

So today, while we have some indication of the regulators’ thought processes, the industry has little formal direction outside of the lessons learned applying mRNA to vaccines. This said, global bodies like the World Health Organization, US Pharmacopeia, and European Pharmacopeia are hard at work. It is also important to remember that a more mature regulatory framework will not manifest until we have more mRNA therapeutics in the late stages of development to help guide the framework.

Finally, we do have very mature guidelines like those for sterility, so while the mRNA-specific regulatory framework must mature to support the anticipated growth of the market, developers are not operating in the dark.

Without question, mRNA therapeutics have a very bright future. These molecules had their moment in the public spotlight, so today’s development news is perhaps a bit less glamorous. Yet, significant and steady progress is being made–mRNA is truly a therapeutic giant that will deliver health landscape-changing impacts for decades.

In addition to all of the advantages of mRNA, including speed, agility, and patient safety, researchers are working to strengthen its weaknesses. For example, lipid nanoparticles (LNPs) are the leading delivery systems that protect mRNA from degradation and facilitate efficient uptake into cells, ensuring that the mRNA reaches its intended target with minimal off-target effects. Ongoing research and development continue to refine LNP formulation and manufacturing to improve processing efficiency, enhance stability, reduce immunogenicity, and improve targeting precision.

Also, innovations in chemical modification, such as incorporating modified nucleosides like psepseudouridineave greatly improved the stability of mRNA molecules and reduced the likelihood of unwanted immune responses. These modifications not only extend the half-life of the mRNA in the body but also ensure that protein production is efficient and controlled.

Finally, researchers at Harvard Medical¹⁰ and certainly other institutions are discovering mechanisms, like specific interleukin-12s, to better control the immune response created by mRNA vaccines, increasing the potency of the response and making it longer-lasting, while decreasing side effects.

Given the promise of mRNA, its proven success, and ongoing work, this mighty molecule’s importance on the therapeutic landscape will not soon fade.

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6. Giara, K. (October 23, 2024). “FDA Approves Moderna’s mRESVIA for Prevention of Severe Outcomes in Older Adults with RSV.” MedCentral https://www.medcentral.com/infectious/ fda-approves-moderna-mresvia-vaccine-for-prevention-of-severe-outcomes-in-older adults-with-rsv
7. (February 14, 2025). “Moderna Reports Fourth Quarter and Fiscal Year 2024 Financial Results and Provides Business Updates.”
8. Moderna. https://investors.modernatx.com/ news/news-details/2025/Moderna-Reports-Fourth-Quarter-and-Fiscal-Year-2024 Financial-Results-and-Provides-Business-Updates/default.aspx Moderna. https://trials.modernatx.com/study/?id=mRNA-1647-P301
9. Yaremenko, A. (January 10, 2025). “Clinical advances of mRNA vaccines for cancer immunotherapy.” Med. https://pubmed.ncbi.nlm.nih.gov/39798545/
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Christian Cobaugh, PhD- Chief Scientific Officer and Founder, Vernal Biosciences

Christian Cobaugh, PhD, has been at the cutting edge of mRNA drug discovery for over fifteen years, which allows him to build connections between customer needs and Vernal’s wide variety of technologies and solutions. He has extensive experience leading discovery and development teams in mRNA technology and was the first Alexion Pharmaceuticals scientist working on their partnership with Moderna Therapeutics to develop mRNA therapeutics. He has directed critical discovery, delivery, development, manufacturing, and quality control activities in the mRNA sector, having led mRNA R&D at Arcturus Therapeutics and Translate Bio, and served as Vice President of Process Development and Manufacturing at Omega Therapeutics.

With 15 mRNA patent applications, Christian brings strong scientific expertise in mRNA and LNP with broad experience in all phases of mRNA therapeutic development and regulatory requirements. He has also authored CMC sections for briefing books and developed ICH Q7-compliant quality management systems.

Christian earned his Ph.D. in Cell and Molecular Biology from the University of Texas at Austin and completed a postdoctoral fellowship at Applied Biosystems in Redwood City, CA.

This article appeared in American Pharmaceutical Review:
Vol. 28, No. 3
April 2025
Pages: 18-21