A Bright Future for RNA Therapeutics
Advances in RNA therapeutics, accelerated by the COVID-19 pandemic, hold promise for personalized treatments against various diseases.
Complete the form below to unlock access to ALL audio articles.
The COVID-19 pandemic changed our society, and the technology that powers it, in an instant. Suddenly, remote working, telehealth and online learning boomed. Other changes took longer to set in – governments are only starting to appreciate the impact of a surge in chronic health conditions. One rapid change was in RNA biology – developing mRNA vaccines against COVID-19 helped us beat the virus into retreat faster than many could have hoped.
The advances in RNA biology since the pandemic could have an enduring impact as well. They promise rapid, personalized and flexible treatments against multiple diseases. But these changes will only be realized if the technology can overcome new hurdles. In this article, we will explore whether RNA therapeutics can realize their full potential. If they do, their impact against COVID-19 will be only an overture.
RNA therapeutics: a promising technology
RNA therapeutics exploit the nucleic acid’s position as a middleman in the central dogma of biology. RNA is required to turn genetic DNA instructions into functional proteins. By introducing custom RNA instructions, incorrect DNA blueprints can be overwritten and new protein products can be generated.
How To Master Lipid Nanoparticle Formulation
Explore important considerations for LNP design, stability and storage.View How To Guide
Classical drug development techniques that produce small-molecule therapeutics are time-consuming processes. The molecules’ surface structure needs to match their intended target receptors carefully. Additionally, only a tiny fraction of the human genome codes for small-molecule drug targets.1 What gives RNA therapeutics an edge is that their base ingredients are so well understood. “We know exactly how to build a piece of DNA or RNA to encode whatever we want,” says Brian Brown, director of the Icahn Genomics Institute at Mount Sinai. RNA can target non-coding genes and transcripts, meaning the druggable space for these compounds is vast. Extensive toolboxes for building RNA means new therapeutics can be designed rapidly.
These are powerful tools, but they once seemed a scientific dead end. In early experiments, cells exposed to external RNA constructs reacted with a powerful and potentially lethal immune response.2 These issues seemed insurmountable – to the extent that mRNA researcher Katalin Karikó was academically blackballed by the University of Pennsylvania for pursuing her research in the area. Karikó would go on to find an innovative solution to the problem. By swapping out a nucleotide from mRNA’s structure for a modified analog that produced no inflammation, she created a molecule that didn’t set off immune alarms. Karikó would go on to share the 2023 Nobel Prize for Physiology and Medicine for her work. In addition to being a tale about the value of sticking to your guns, Karikó’s discovery was also the breakthrough that helped RNA biology enter a golden age, says John Cooke, medical director of the Center for RNA Therapeutics at Houston Methodist.
A silver lining to COVID-19
Manufacturing High Quality and Purity Antibody–Drug Conjugates
Discover proven strategies to maintain ADC potency and purity at scale.View Webinar
After this immune roadblock was overcome, the technology blossomed. A variety of RNA therapeutics have since been designed. These include RNA interference (RNAi) molecules, which can block transcription of target genes; antisense oligonucleotides, which interfere with mRNA production; and RNA aptamers, which bind to intra- and extracellular targets with affinity and specificity matching that of antibodies.3,4,5
Alongside mRNA therapeutics, these technologies have been iteratively improved over the 20 years since Karikó cracked the code of safe RNA therapy. But these advancements went unheralded by the wider public until the COVID-19 pandemic. When the time came for the rapid development of a novel vaccine, RNA therapeutics stepped up to the task.
Now, the technology is firmly in the public spotlight. This higher profile has turbocharged progress in the field. Of the 17 RNA therapeutics approved by the FDA, 9 have been given the green light in the last 5 years.6 It’s “a silver lining to the COVID crisis,” says Cooke. The new challenge is to maximize RNA therapeutics’ potential.
A safe delivery
Achieving Cell and Gene Therapy Excellence
Discover tools and strategies for ensuring therapeutic quality.View Compendium
Samir Mitragotri, a professor of bioengineering at Harvard University, says that delivering RNA therapeutics to their intended targets is now the field’s biggest challenge. “These molecules are not super stable,” he adds. “They are susceptible to degradation. They are large compared to other therapeutics.”
These factors become even more important when you consider the impact of a misdirected therapeutic. Small-molecule drugs, like aspirin, will leave the body rapidly, so their effects on off-target tissues are also short-lived. RNA therapeutics, by kickstarting or stopping gene transcription, can have longer durations of action. “The burden of making sure that it goes to the right place is really high,” says Mitragotri.
But before they act on their targets, RNA therapeutics have to reach them in the first place. That’s not straightforward. The molecules are at the mercy of proteins called nucleases in the bloodstream that easily break them down. A solution for the problem came from nanoscience.
Lipid nanoparticle (LNP) technology isn’t new. The first FDA-approved drug that utilized the technology – the antifungal amphotericin B – is over 30 years old. But it was only in 2018 that the RNAi-based compound patisiran, the first such drug to be encapsulated in LNPs, was approved to treat the neurodegenerative condition transthyretin-related hereditary amyloidosis.7 LNP technology traps therapeutic RNA inside lipid shells. This protects the RNA from nucleases, stabilizes the molecule and helps it pass through lipophilic membranes.8 The technology was used in Pfizer and Moderna’s COVID-19 mRNA vaccines. “I think that the unsung hero, at least of the [mRNA] vaccines, is really this delivery system,” says Brown.
Washed away
Other innovations have taken different routes toward protecting RNA. One approach is to change the linear structure of therapeutic RNA molecules, instead making them circular, as the nucleases that chew up RNA bind onto the molecule 5’ or 3’ end.9 “If you have a circular RNA, there's no end. So the exonucleases can't gain purchase and the RNA lasts longer,” says Cooke, whose lab has been experimenting with this new structure.
Though technologies like LNPs have improved RNA therapeutics’ durability, they can’t bypass other challenges in drug delivery. Mitragotri says the challenge facing RNA–LNP complexes in the bloodstream is similar to that facing someone washed away down a mighty river. The complex’s target is on the blood vessel’s “bank”, but they lack an anchor that will get them close enough to bind. Mitragotri highlights a strategy in which LNPs “hitch a ride” on passing red blood cells, which bump against blood vessel walls when they diffuse oxygen into tissues.10 “We have designed ways to allow the nanoparticles to attach to red blood cells and circulate in the blood for a longer time and be able to target the tissue,” he explains.
If these technologies improve RNA therapeutics’ stability and targeting, there could be rapid benefits to the health system. Cooke outlines a new program at Houston Methodist using mRNA vaccines to target cancer. This approach can create new vaccines quickly, and Cooke says that the team intend to develop, generate and administer cancer vaccines within the same hospital – something he thinks is a world first.
Cooke hopes that this approach could become commonplace within a decade. “You'll have university-based programs where you can have these deployable manufacturing units that can generate clinical-grade RNA on a desktop. [...] These desktop apparatuses will generate personalized RNA therapeutics,” he says.
Mitragotri is similarly optimistic. He points out that having many different RNA tools – be it siRNA, mRNA, circular constructs or hitchhiking molecules – will be essential if the field is to tackle the grand challenges of human disease. “We need a relatively wide basket of technologies to support that variety of applications,” he concludes.
