EnPlusOne Biosciences is breaking the RNA drug bottleneck by enabling RNA oligonucleotide manufacturing at scale with a smaller environmental footprint.
The Problem
RNA drugs are the next frontier of medicine, capable of turning genes on or off, replacing dysfunctional proteins, and delivering drugs to their targets. But manufacturing the oligonucleotide “building blocks” of RNA still relies on an antiquated chemical synthesis process that is expensive, labor-intensive, inefficient, and produces metric tons of toxic chemical waste. These problems are currently limiting the ability of lifesaving RNA drugs to be made and delivered to patients who need them.
Our Solution
A research team at the Wyss Institute led by George Church, Ph.D., has developed a new enzyme-based, template-independent RNA oligonucleotide synthesis technology (eRNA) to overcome the limitations of traditional chemical synthesis. Their scalable, flexible, and cost-efficient synthesis method uses a set of proprietary engineered enzymes and novel nucleotide building blocks to produce accurate, high-quality RNA oligonucleotide sequences that can include both natural and non-natural bases at high efficiencies. It is also conducted in water rather than in harsh chemical solvents, making it a substantially “greener” approach to oligonucleotide synthesis. eRNA enables the synthesis of highly customized and significantly longer RNA oligonucleotides than current methods, and can stabilize RNA products, endow them with new properties, and facilitate delivery to their molecular targets within the body.
eRNA was licensed by the Wyss startup EnPlusOne Biosciences in 2022.
Product Journey
The concept for eRNA started as a causal conversation between colleagues in the lab. Jonathan Rittichier, Daniel Wiegand, and Erkin Kuru recognized that the pharmaceutical industry was in the midst of an RNA revolution. Because their lab had previously devised a way to synthesize DNA using enzymes, and hypothesized they could do the same for RNA and help meet the growing demand for custom RNA molecules.
The team engineered an enzyme from the yeast Schizosaccharomyces pombe that is known to link nucleotides together to form strands of RNA, making it more efficient and capable of incorporating non-standard nucleotides into RNA. This was especially important, as every FDA-approved RNA drug contains nucleotides that have been modified from their original form. They also created a new set of nucleotides whose binding sequence they could easily control in a water-based solution, which reduced the synthesis process from four steps to two.
The researchers demonstrated that their new process incorporated nucleotides with 95% efficiency, which is comparable to chemical synthesis. The team then iteratively repeated cycles of enzymatic RNA synthesis to build molecules of up to 23 nucleotides long, which is the size of many blockbuster RNA therapeutics.
Based on its potential to revolutionize the production of RNA drugs, eRNA was named a Validation Project in 2019 and 2020, and in 2021 was chosen as the first project to receive support through the Laboratory for Bioengineering Research and Innovation as part of the Wyss Institute-Northpond Labs alliance. It launched from the Wyss Institute in 2022 as EnPlusOne Biosciences with a successful Series Seed Financing of $12 million led by Northpond Ventures, co-founded by Rittichier, Wiegand, Church, and Dan Ahlstedt.
Impact
Since launching, EnPlusOne has successfully synthesized the commercially approved siRNA drug Leqvio® (inclisiran), which is used to treat high cholesterol in millions of patients, using its water-based ezRNA™ platform. It was also able to incorporate more than 50 modifications to the RNA antisense strand, demonstrating its platform’s ability to unlock a wide range of novel RNA therapeutics. Ahlstedt, Rittichier, and Wiegand are part of the Wyss Lumineers Class of 2022.