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The messenger RNA (mRNA) vaccines that helped control the COVID-19 pandemic didn’t come out of nowhere. For decades after mRNA was first isolated in the 1960s, scientists worked to understand how it might help fight disease — using the body’s instruction manual to replace defective proteins or produce new, helpful ones.
“We realized that we could use the same mechanism that the body uses to treat almost any disease,” says Pieter Cullis, a biochemist at the University of British Columbia in Vancouver. “It’s a very powerful approach.”
Many lines of research coincided to help propel mRNA to the forefront. “Scientists have long been working on mRNA based on its promise,” says says Linda Maithiasson, strategic customer leader for nucleic acid therapeutics at Cytiva — a life sciences tools and services supplier. “The innovation acceleration caused by COVID, alongside other advances such as CRISPR, enabled mRNA to be adopted quicker than other traditional molecules.”
Those advances, and the challenges they solved, form the history of mRNA vaccines and how they became part of mainstream medicine. Now scientists and doctors are looking beyond COVID-19 to the almost limitless potential of nucleic-acid-based drugs. “mRNA is a very promising tool for a variety of diseases,” says Maithiasson. “We have seen success in vaccines. To unlock its full potential, delivery and targeting will be crucial. There it is still a lot of work needed.”
The delivery issue
Using mRNA, or any nucleic acid, as a drug requires overcoming several hurdles. First, it is easily degraded in the body. If RNA is simply injected into a person, it is quickly broken down before it can get into cells to create proteins. It needs some kind of delivery system.
Cullis helped design these systems. In the 1980s, he was working on lipid nanoparticles (LNPs) as a delivery system for cancer drugs, but as interest in gene therapy began to take off in the 1990s he moved in that direction. He thought the tiny capsules would be an ideal way to protect nucleic acids from degradation.
But they brought their own difficulties. To get the negatively charged nucleic acids to associate with the LNPs, the lipids themselves needed to be positively charged – which made them toxic. Cullis’s solution was to develop an ionizable cationic lipid that would be positively charged in a low pH environment but neutral at physiological pH. That allowed researchers to load the DNA or RNA at low pH, and the nucleotides would remain associated with the nanoparticle at neutral pH.
“We got away from the toxicity problem, and it turned out that this really had legs,” says Cullis.
The second hurdle was that mRNA was strongly immunogenic. Drew Weissman and Katalin Karikó at the University of Pennsylvania came up with a solution in 2005. They chemically modified the RNA, swapping out the uridine nucleoside for a synthetic pseudouridine. This not only reduced the immunogenicity, but also led to greater production of protein in the target cell.
“This was a major turning point, which really started to unlock the potential of mRNA, and was one of the key enablers for advances to come,” says Maithiasson.
Proving ground
The first test for LNPs and RNA drugs was not a vaccine but a treatment based on short interfering RNA (siRNA), non-coding double-stranded pieces of RNA that can silence specific genes. In 2012, the biotech company Alnylam Pharmaceuticals started clinical trials of patisiran, a siRNA drug that treats hereditary transthyretin-mediated amyloidosis, a neurodegenerative disease caused by a defective gene. Patisiran is encapsulated in an LNP to protect it until it reaches the liver, where it then prevents expression of the defective gene. Patisiran was approved in the United States and Europe in 2018.
The years spent on the development of this small-molecule RNA drug jump-started work on mRNA vaccines. “You can see its reflection in the vaccines in use today,” says Daniel Anderson, a biomedical engineer at the Massachusetts Institute of Technology in Cambridge, who works on nucleic acid drugs.
The first mRNA vaccines targeted other viruses. In 2014, Weissman successfully used nanoparticles produced by Acuitas Therapeutics, a company co-founded by Cullis, for Zika and flu vaccines in animal models. This work was ongoing when the COVID-19 pandemic struck in 2020.
All efforts were redirected to face this new, huge threat — and the advantages of mRNA vaccines made themselves known. Within weeks of publication of the coronavirus’s genetic sequence in early 2020, both Pfizer-BioNTech and Moderna were developing vaccines targeting its spike protein. After clinical trials and FDA emergency use authorization, the first COVID-19 vaccine shots were in patients’ arms before the end of the year — a stark contrast with the usual years-long vaccine development schedule.
Now that the value of mRNA therapies has been shown, labs and pharmaceutical companies are branching out into dozens of other therapeutic areas. “RNA can code for any protein, so it can be suitable for such a broad range of applications and diseases,” says Maithiasson. “The fact that it is a cell-free process and that the doses are low, makes the manufacturing both quicker and smaller.”
New horizons
In the near term, Anderson expects to see COVID-19 vaccines optimized for other SARS-CoV-2 variants. “The beauty of these vaccines is how quickly they can be adjusted to deal with new forms of the virus,” he says. And there are a host of other mRNA vaccines in the works, for diseases ranging from influenza to HIV to cancer.
But mRNA doesn’t have to be in a vaccine. Researchers are working on treatments for genetic diseases like cystic fibrosis, or liver and muscular diseases. And mRNA may have a role in genome editing as well. Anderson has used mRNA encoding the CRISPR-Cas9 system to permanently inactivate a gene in the liver of mice; the biotech company Intellia Therapeutics recently showed that it worked in humans as well (Gillmore, J.D. et al. NEJM 385; 2021). “It’s a tremendously exciting demonstration of how mRNA nanoparticles may lead to genomic correction for disease,” says Anderson.
Cullis predicts a variety of uses for mRNA as a therapeutic agent. It could be used as a personalized cancer vaccine to target mutant proteins in specific individuals. Or it could lead to in vivo CAR-T cell cancer therapies. Direct injections into the brain could treat diseases like Alzheimer’s, Huntington’s and Parkinson’s diseases, he predicts.
“All of these new potential medicines are coming into focus now,” says Cullis. “It’s an extraordinarily exciting time.”