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:
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.
Judy Savitskaya is the cofounder of a stealth startup.