Blog January 31, 2022

What’s Next for mRNA?

Vaccines and the next-generation of mRNA technologies

The field of mRNA drug development had its major breakthrough in 2005 when scientists determined how to escape immune responses degrading foreign synthetic RNA, thus prolonging its stability and its ability to yield new protein. That work inspired the founding of Moderna and BioNTech, companies that were able to successfully apply their mRNA know-how to quickly develop and produce effective vaccines against COVID-19. Today, both companies have extensive pipelines of mRNA-based vaccines and therapeutics under development for infectious diseases as well as other important indications, including cancer, heart disease, and autoimmune and inflammatory conditions. At the same time, new start-ups like Laronde and Orna Therapeutics are raising significant capital to fund the next-generation of mRNA technologies with a focus on longer-lasting and more complex applications, while several larger pharma and biotech firms, including Sanofi and Sinopharm, are developing their own mRNA capabilities

Prior to the COVID-19 pandemic, both Moderna and BioNTech had been exploring applications of mRNA against other infectious diseases, and that work has continued. Moderna has a large pipeline of infectious disease vaccines that go beyond next-generation COVID vaccines (including those against the rapidly spreading Omicron variant) comprise such products as influenza, respiratory syncytial virus (RSV), pan-respiratory viruses, and combination vaccines for COVID and influenza. The company is also developing vaccines for more complex viruses, such as cytomegalovirus (CMV–a major cause of birth defects, for which Moderna initiated a pivotal trial in November 2021), Zika and HIV. Likewise, BioNTech has a rich portfolio of infectious disease vaccines in development, and is partnering with Pfizer on influenza and with the Bill and Melinda Gates Foundation on HIV and tuberculosis, as well as developing a malaria vaccine on its own. In November 2021, BioNTech collaborators at Yale announced results of research on a prototype mRNA vaccine that, when tested in a guinea pig model, provided protection from tick-borne diseases like Lyme Disease by delivering genetic instructions that taught the immune system to recognize and fight proteins found in tick saliva.

Both BioNTech and Moderna were founded with a primary focus on cancer. Both companies are still pursuing personalized cancer vaccines designed to elicit a strong T cell response by expressing neoantigens found in an individual patient’s particular tumor. Big pharma has shown strong interest in supporting these efforts, with Moderna partnered with Merck, and BioNTech with Roche/Genentech. Moderna and Merck are also studying the potential of such personalized vaccines to improve the efficacy of checkpoint inhibitors, with clinical studies of mRNA-4157 in combination with Keytruda underway in melanoma. 

Research suggests mRNA technology will also have important therapeutic applications beyond cancer. Moderna partnered with AstraZeneca in 2013 to develop mRNA-based therapeutics for the treatment of serious cardiovascular, metabolic, and renal diseases as well as cancer. The most advanced of these applications leverages mRNA encoding VEGF, which promotes new blood vessel growth. The mRNA is locally administered into a patients’ heart during a coronary bypass surgery to promote heart tissue regeneration following heart failure. While data from an early Phase 2 trial was too limited to discern a therapeutic effect, results presented at the American Heart Association meeting in November 2021 showed the mRNA treatment was well tolerated and could promote localized production of VEGF. Moderna also announced a collaboration with Metagenomic in November to combine Metagenomic’s gene editing tools with Moderna’s mRNA platform and lipid nanoparticle delivery technology to develop gene editing therapeutics for patients with serious genetic diseases. 

Autoimmune and inflammatory diseases are also growing areas of interest for mRNA developers, although at earlier stages of development. In January 2021, BioNTech published a study in Science showing that an mRNA vaccine had the potential to treat multiple sclerosis (MS) without suppressing the immune system as existing MS therapies do. Asthma, in addition to MS, is also an interest of newer mRNA companies Translate Bio and Ethris.    

Many of these newer applications require longer-acting mRNA molecules that encode multiple proteins capable of driving different activities, rather than the single function performed by the currently available vaccines against COVID-19. Native mRNA is very short-lived in the body and already the COVID-19 vaccines have required a chemical modification of the mRNA molecules allowing them to remain stable and active for a few days, rather than hours. Several companies, including BioNTech and Gritstone, as well as academic laboratories, are now developing longer acting mRNAs capable of self-replicating within the cell, further extending their activity into the weeks range. As a result, these second generation mRNA therapeutics can provide higher levels of antigen over time and with a lower initial dose compared to their first generation counterparts, thus potentially reducing the risk of adverse events. 

Other approaches to self-replicating mRNA therapeutics, such as those under development at Strand Therapeutics, aim to encode “genetically programmed logic circuits” that enable the mRNA therapeutic to act conditionally and potentially deliver a series of actions. Strand aims to turn protein expression ‘on’ or ‘off’ within a specific intracellular environment depending on cell-type specific biomarkers, enabling control over the location, timing and intensity of protein expression. While Strand’s programs are currently in preclinical development, the company aims to enter the clinic with an initial therapeutic candidate for cancer sometime this year.