The Second Coming of RNA Medicines

Judy Savitskaya

The RNA technology underlying both the Moderna and Pfizer/BioNTech vaccines could give us our fastest ticket out of the COVID-19 pandemic. With their rapid development and the early signs of success, RNA-based therapeutics are enjoying a well-deserved moment in the public and scientific spotlight. However, this is not the first time that RNA drugs have garnered excitement and investment. Back in the early 2000’s there was a huge wave of excitement around RNA technology, and several high profile companies launched with the promise to harness the therapeutic potential of RNA. However, this wave died down after a slew of thorny technical and biological challenges slowed development and implementation.

So what is different about this moment? The rapid release of multiple RNA vaccines provides the much needed proof of the power of this approach — not just for this pandemic, but for the entire class of drugs. The vaccines are generating data, know-how, and infrastructure — which paves the way for existing and new RNA drugs.

As a refresher, one of RNA’s essential roles is to act as a stepping stone between the DNA that encodes information and the proteins that carry out the genetic program. The majority of drugs we currently use to treat disease bind to disease-related proteins and inhibit their function. RNA-based drugs, on the other hand, work earlier in the process at the RNA level, before the protein is made. This means we can modify the production of disease-related proteins, rather than just blocking function. RNA drugs can turn up protein levels, turn them down, modify their sequences, and even encode entirely new proteins. This gives RNA drugs the potential to have larger and more diverse effects on the cell and on disease. RNA-based drugs are both made of RNA and target RNA and typically fall into three categories: RNA interference (RNAi/siRNA, which degrade target RNAs), antisense oligonucleotide (ASO, which either alter RNA and thus protein sequence or degrade RNA), and messenger RNA (mRNA, which encode new proteins, such as the coronavirus spike protein).

Despite two decades of hard work, only a few RNA drugs had been approved by the FDA prior to the COVID-19 vaccines and none were from the mRNA category. But COVID-19 vaccine development flipped this field on its head, going from inception to approval within a single year. This was a high-stakes fulfillment of the key promise RNA companies had made — that once we know what protein needs to be targeted, new RNA medicines can be designed and developed much, much faster than traditional drugs. 

This was a high-stakes fulfillment of the key promise RNA companies had made — that once we know what protein needs to be targeted, new RNA medicines can be designed and developed much, much faster than traditional drugs.

Prior to 2020, the number of patients who had received an RNA drug was in the thousands, but just in the last few months since the vaccines’ approvals, this has jumped to the tens of millions! The massive scale of deployment and adoption we’re seeing will help validate and accelerate the field of RNA therapeutics in several concrete ways:

  • RNA Delivery – the primary blocker for the field of RNA medicines is the challenge of delivering RNA molecules to a desired organ or cell type. RNA molecules do their work inside of cells and don’t easily cross cellular membranes. Both of the COVID-19 mRNA vaccines use lipid nanoparticles (LNPs) to deliver these RNA molecules into liver cells where they have their therapeutic effect. LNPs are used to deliver the FDA-approved RNA drug Onpattro, but the COVID-19 vaccines introduced new formulations for LNPs into large patient populations, further derisking LNPs as a delivery modality. We now have more data on the activity and safety of LNPs in patients as well as the infrastructure to produce LNPs and encapsulate RNA at larger scales. 
  • RNA Manufacturing – manufacturing processes for RNA and the LNPs used to deliver them are very different from traditional drug manufacturing systems. These novel, subscale manufacturing processes were partially responsible for the famously high cost of the first generation of RNA therapeutics. However, we now have large scale manufacturing operations that were constructed for the COVID-19 vaccines. Furthermore, these vaccine manufacturing programs have heavily relied on outsourcing, so there is now an ecosystem of vendors with capabilities already in place. Tools and production systems, as well as teams and companies, that were built for the COVID-19 vaccine projects can be repurposed for other RNA therapeutics.
  • RNA Stability and Expression – RNA is unstable and can get degraded by a plethora of natural human enzymes. RNA drugs use chemical modifications to prevent degradation and extend the drugs’ half life. But delivery and stability are only half the battle, as these therapeutic RNAs must still perform their key functions despite the modifications. While pre-clinical work and early clinical trials can give some insight into whether these stabilizing changes are effective, the true test is deployment in large numbers of patients. We now have definitive proof of successful protein expression and sufficient half life in a large patient population with varying genetic backgrounds and pharmacokinetic dynamics. 
  • Safety – as with any new modality, safety and toxicity are major risk factors. It’s hard to predict how exactly a new molecular entity may interact with non-target molecules in the human body. Again, thanks to the massive deployment of mRNA vaccines in a heterogeneous population, there is increased confidence in the safety of RNA drugs as a class. However, as with all drugs, each specific usage will still need to undergo rigorous safety profiling.

Of course, the field of RNA therapeutics still has several important open challenges. First, delivery to organs other than the liver remains a major hurdle, as LNPs naturally accumulate in the liver. Several groups are working on engineering LNPs for increased delivery to other organ targets and decreased liver delivery, though this has proven difficult. New technologies outside of the LNP field have been proposed to solve this problem, primarily targeting delivery to the central nervous system or muscle, though few clinical programs have shown progress. Second, immunogenicity of the RNA molecules is a potential toxicity risk. The COVID-19 vaccines don’t directly validate this aspect of the modality, as vaccines are designed to intentionally engage the immune system, while most drugs need to evade the immune system. Some progress has been made on minimizing immunogenicity, as validated by the existing RNA drug approvals, but more work is needed to establish design principles for avoiding immunogenicity. Third, the vaccines are given in one or two doses, while most other therapeutics will require regular re-dosing, potentially for the rest of a patient’s life, so safety issues that may arise following a long period of repeat dosing also requires further investigation. 

While some hurdles remain, it’s incredible to see how the path to the clinic can be cleared for an entire therapeutic class due to the success of individual programs. In the case of the COVID-19 vaccines, the massive scale and speed of the design, manufacturing, and testing of these drugs has created tailwinds for all other RNA drug makers.

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