Advertisement

If you have an ACS member number, please enter it here so we can link this account to your membership. (optional)

ACS values your privacy. By submitting your information, you are gaining access to C&EN and subscribing to our weekly newsletter. We use the information you provide to make your reading experience better, and we will never sell your data to third party members.

ENJOY UNLIMITED ACCES TO C&EN

RNA

Start-up proposes enzymatic RNA synthesis for oligonucleotides

EnPlusOne says RNA makers need a new production process to meet rising demand

by Matt Blois
October 14, 2022 | A version of this story appeared in Volume 100, Issue 37

 

EnPlusOne scientists in their lab working on making RNA with enzymes.
Credit: Wyss Institute at Harvard University
EnPlusOne says that, unlike chemical RNA synthesis, its enzymatic process doesn't use hazardous chemicals, so the team doesn't need protective gear. CEO Daniel Wiegand is standing in the middle.

The number of people using RNA-based therapeutics is set to increase substantially as new drugs reach the market, and companies are looking for ways to scale up RNA production.

In September, a team from the Wyss Institute at Harvard University raised $12 million to launch EnPlusOne Biosciences, a firm developing a process for making RNA with enzymes instead of chemistry. Conventional manufacturers are also expanding. Bachem, for example, is spending $760 million to build a plant in Switzerland that will make peptides and oligonucleotides like RNA.

The main RNA therapeutics are antisense oligonucleotide (ASO) and RNA interference (RNAi) drugs—small, modified RNA molecules that bind to RNAs in the body, preventing them from producing a protein. The US Food and Drug Administration approved the first ASO drug in 1998. Approvals have picked up in recent years; two ASO drugs and two RNAi drugs were approved between 2016 and 2019.

Early RNA drugs were for rare diseases, but that’s changing, says EnPlusOne CEO Daniel Wiegand. The consulting firm Bain & Co.tallied 282 ASO and RNAi drugs in clinical trials, with nearly half in Phase 2. “They’re moving into bigger patient populations,” Wiegand says. “We need new ways to access metric tons of this material.”

RNA is usually made using phosphoramidite chemistry, which adds nucleotides to a sugar-phosphate backbone one by one. Sabine Müller, an oligonucleotide production expert at the University of Greifswald, says this process works for small-scale output but will be hard to scale up because it requires lots of hazardous chemicals. “We’re at a point where the industry thinks we need procedures that are more sustainable,” she says.

Companies making long strands of messenger RNA (mRNA) for vaccines have already achieved large-scale production with a different process. They start with a DNA template and use an enzyme to transcribe the template into mRNA. Müller says the approach works for long strands of mostly unmodified mRNA, but it can’t easily handle the modifications ASO or RNAi drugs need to remain stable in the body.

Wiegand says the enzymatic process will reduce the chemicals needed for RNA synthesis, making it easier to set up large-scale production. And unlike mRNA manufacturing, EnPlusOne’s process doesn’t require a DNA template but can make RNA directly from basic building blocks.

But EnPlusOne is still operating at laboratory scale, producing only a few milligrams of RNA at a time. Müller warns that enzymes can be fickle and scaling up won’t be easy. She says researchers are also trying to reduce reagent use in chemical synthesis. One option is making RNA from premade blocks of three to four nucleotides rather than from single nucleotides.

In addition to reaching larger scale, new RNA manufacturing platforms will need to be flexible enough to incorporate new molecular modifications developed by drug companies, according to Anshul Rana, an associate partner at Bain. “There’s an evolution of the manufacturing process that comes along with the evolution of therapeutics,” he says.

Article:

This article has been sent to the following recipient:

0 /1 FREE ARTICLES LEFT THIS MONTH Remaining
Chemistry matters. Join us to get the news you need.