RNA – Opportunities & Challenges

At this point, mRNA vaccines need no introduction; the dramatic success of the SARS-CoV-2 mRNA vaccines has been nothing short of phenomenal. More vaccines (including personalized immunotherapies for cancer), and critically, an even broader class of mRNA therapeutics lie right behind. From mRNA protein replacement therapies for diseases like cystic fibrosis and methylmalonic aciduria, to applications in surgery, delivery of mRNA as a therapeutic is ready to revolutionize medicine.

The manufacturing of mRNA on >100 kg scales has also been nothing short of phenomenal. To enable emerging biomedicines, such manufacturing needs to be reduced in cost and distributed world-wide, democratizing access. All of the mRNA vaccines to date have been synthesized using the enzyme T7 RNA polymerase, coincidentally the enzyme that the Martin lab has studied for decades.

The Toll-like receptor TLR3 binding to long dsRNA (PDB: 3CIY)

One of the primary barriers in the synthesis/manufacturing of RNA is the unintended production of double stranded RNA impurities. While these impurities are not harmful in themselves, our bodies have evolved a first line defense system (the innate immune response) that sees double stranded RNA as evidence of a viral attack (many viruses that infect us are double stranded RNA viruses). Tricking the immune system into thinking it is being attacked can be good for vaccines (though too much is not good!). For other purposes, this response, which triggers inflammation, can destroy the utility of an otherwise game-changing therapy.

Double stranded RNA is not an intended product of RNA synthesis and batch-synthesized RNA must be purified to reduce dsRNA to acceptable levels. We have a different idea: change the reaction so that dsRNA is not produced in the first place! Read more here…