The future outlook for mRNA therapies

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Reece Armstrong explores the potential and future opportunities for mRNA-based therapies.

Messenger RNA (mRNA) has come into focus within the drug discovery and development as an exciting tool to deliver genetic information. Whilst research into mRNA has been ongoing for decade, interest has sparked in recent years and research has begun to expand into areas of vaccinology, infectious diseases and other indications. 

The biggest growth driver for mRNA therapeutics came from the Covid-19 pandemic, when mRNA-based vaccines proved effective in treating SARS-CoV-2, and pharmaceutical companies such as Pfizer/BioNTech and Moderna were successful in bringing these treatments to market.

For instance, consider how at the end of 2018, the mRNA therapies market was valued at $3.43 billion according to Visiongain research, a figure which has risen to approximately $40 billion in valuation today according to Statista, and which represents the enormous gains this market has seen within the last five years. 

Yochi Slonim, CEO of Anima explains further: “The impact of the Covid-19 pandemic on mRNA research has been significant, fundamentally altering the landscape of therapeutics. The widespread recognition of the term “mRNA” by people around the world can be attributed to the development of Covid-19 vaccines.”

Slonim states that the pandemic helped to trigger a “resurgence in mRNA research and drug development,” the results of which have “provided strong validation for the potential of mRNA biology in the discovery of drugs and vaccines.” 

But what is mRNA?

mRNA is a molecule made up of a single strand of ribonucleic acid (RNA). Its job is to carry coding information that is essential to the translation and processing of functional proteins. This is essential to its use as a therapeutic agent and gives the technology a vast versatility making it suitable to treating a wide range of diseases – especially those that have high protein expression. mRNA-based approaches can produce proteins / peptides by using protein synthesis which is processed in a transfected cell1. 

mRNA exists in every cell within the human body and this, along with its role in the development of proteins, are the reasons why mRNA therapies have such potential in treating many diseases. Proteins perform myriad functions within the human body and scientists have estimated that there are at least 20,000 canonical proteins that we know about. Their functions such as carrying oxygen, providing structural support to cells, transmitting biological processes to cells, and fighting viruses and bacteria, are essential to human health. If the body fails to make the right protein, diseases such as cancer, type II diabetes, neurological conditions, and metabolic diseases can occur.

As such, teams are now researching a variety of medical applications for mRNA-based drugs. One notable area has been in the area of vaccines, where mRNA vaccines have gained interest in infectious diseases and also cancer. mRNA can be used alongside CAR-T cell therapies and target specific cell types associated with diseases, including cardiac cells, bloods, hepatocytes and neurons2.Other potential areas include mRNA being used to produce therapeutically active proteins or even as a protein replacement option when mutated proteins are   affecting the normal functioning of a body. 

Discussing how versatile mRNA-based are, Slonim explains that “the industry has been increasingly recognising that mRNA biology, which plays a fundamental role inside cells, can serve as a foundation for discovering treatments across a wide spectrum of diseases and therapeutic areas.” 

“This recognition has led to the development of programs encompassing vaccines, RNAi, and small molecules that span diverse therapeutic areas. It’s worth noting that the approach of small molecules interacting with mRNA biology represents a relatively new and potentially broader and more effective strategy. This novel approach allows for the modulation of mRNA biology to either increase or decrease protein production, offering the versatility to target a wide range of mechanisms of action (MOA),” Slonim states. 

We can see this versatility in the various treatments that are currently being researched. At the start of 2024, the first patients in a clinical trial investigating an mRNA cancer therapy were dosed.

The Mobilize trial is investigating the mRNA-4359 therapy and its potential for treating melanoma, lung cancer and other solid tumour cancers. The study is assessing the use of mRNA-4359 both by itself and as a combination treatment alongside the immune checkpoint inhibitor pembrolizumab.

Whilst results from the study won’t be available for a number of years, Dr David Pinato, a Clinician Scientist at Imperial College London and Consultant Medical Oncologist at Imperial College Healthcare NHS Trust, and investigator of the UK arm of the trial, said that the “trial is laying crucial groundwork that is moving us closer towards new therapies that are potentially less toxic and more precise.”

This year too saw researchers from University College London (UCL), King’s College London, and Moderna, use mRNA to create a therapy for a rare liver disease. 

In preclinical mice studies, the teams discovered that mRNA could correct a rare genetic liver disease known as argininosuccinic aciduria, which affects how the body breaks down protein and which can lead to high levels of ammonia in the blood. Patients with argininosuccinic aciduria can also experience an imbalance of glutathione regulation, which is important for liver detoxification.

Rare diseases are largely treated using gene therapies which employ modified viruses to bring the therapy to the disease cells. However, these therapies can cause severe adverse effects. 

In the study, the teams used a microdroplet of lipids to protect the mRNA and inject the mice with the therapy, targeting the liver cells. Benefits of the treatment lasted around seven days and the procedure was performed once a week over the course of eight weeks. The researchers would expect that if used in humans, there would be a longer gap between the treatment courses. The mice given the treatment survived for over three months.

Co-lead Principal Investigator, Dr Julien Baruteau (UCL Great Ormond Street Institute of Child Health), says: “mRNA has revolutionised the field of vaccines during the Covid-19 pandemic. We believe it can now do the same for rare diseases.”

“We have shown that mRNA holds an unprecedented therapeutic potential for incurable genetic diseases, in particular liver conditions. We aim to apply this approach to other inherited liver diseases and translate mRNA therapy to patients, especially in children.”

Within drug discovery, mRNA also presents researchers with the opportunity to be used as diagnostic tool for disease signatures. For example, mRNA testing can offer deeper insights compared to DNA and give researchers a better understanding of gene expression in relation to certain cancers. By understanding mRNA as a fundamental process in the formation of healthy or diseased cells, it’s possible that researchers can determine which therapeutic routes to take to treat patients, and also develop therapies targeting specific causes of disease. 

“Understanding mRNA biology by visualising mRNA life cycle events has the potential to revolutionise drug discovery. By taking images of diseased cells and comparing them to healthy ones, it becomes possible to visually identify mRNA regulatory pathways that differentiate both states – revealing the underlying cause of disease biology that can be named “disease signature,” Slonim explains. 

Slonim iterates how this is now happening at the beginning of drug discovery processes, enabling researchers to screen for molecules that “shift from diseased cells towards healthy phenotypes.”

“Initial hit compounds would then be considered promising candidates from the beginning since they target a disease-relevant pathway phenotype with a preconceived notion for their mechanisms of action,” Slonim says. 

The benefits of mRNA 

mRNA-based therapies have multiple benefits over existing DNA and protein platforms. The fact that mRNAs are transiently expressed – meaning the proteins that produced are done so in a short period–  along with the fact that MRNA doesn’t integrate into the host genome, gives these therapies a high safety profile with less chance of mutagenesis. mRNAs also have a longer lasting expression of the therapeutic proteins, when compared to direct protein delivery, giving them a longer clinical benefit3. 

The future of mRNA therapies 

As of last year, there were over 190 organisations involved in the development of 310 mRNA vaccines and therapeutics across a range of disease areas. mRNA-based vaccines accounted for 65% of this work with therapeutics taking the remaining 35%. As such, it’s clear that there is great scope of drug discovery and development within the sector. Regarding its potential, it’s believed that mRNA drugs present limitless opportunities to treat diseases, and that mRNA will become a dominant platform for prophylactic vaccines within the next 15 years2.

Speaking about the future outlook for mRNA therapies and RNA-based therapies, Dale Patterson, VP and General Manager of Molecular Biology and Nucleic Acid Therapeutics at Thermo Fisher Scientific, says: “While mRNA only recently entered the mainstream with the speedy development of mRNA-based Covid-19 vaccines, scientists have been studying the clinical use of ribonucleic acid (RNA) for decades. Since the discovery of RNA as an essential molecule for life, researchers have made incredible progress in using RNA as a novel therapeutic modality to produce RNA-based therapeutics and vaccines to target the source of disease for a variety of conditions. Today, there are several other categories of RNA therapeutics with drugs already approved or currently in development. These include RNA interference (RNAi), RNA aptamers and antisense oligonucleotides (ASO). While there are more than 90 mRNA-based drugs currently in clinical trials, there are around a dozen drugs using different types of RNA in development as well. What’s really exciting is how quickly these drugs are able to move through clinical trials, as we saw with Covid-19 vaccines, compared to other types of therapeutics.”

DDW Volume 25 – Issue 2, Spring 2024

References

  1. Qin S, Tang X, Chen Y, et al. mRNA-based therapeutics: powerful and versatile tools to combat diseases. Sig Transduct Target Ther 2022;7:166.
  2. Wang YS, Kumari M, Chen GH, et al. mRNA-based vaccines and therapeutics: an in-depth survey of current and upcoming clinical applications. J Biomed Sci 2023;30;84.
  3. https://www.thermofisher.com/blog/behindthebench/mrna-therapies-current-landscape-and-future-possibilities/

Reece ArmstrongAbout the author

REECE ARMSTRONG is Editor of DDW. He has worked in life sciences and pharmaceutical B2B publishing for seven years and was previously Editor of European Pharmaceutical Manufacturer. He has a master’s degree in Journalism from Newcastle University.

 

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