By Vivienne Raper, PhD

British-based researchers are hoping to reduce the costs of mRNA production by expanding the range of manufacturing techniques. A team has created and are testing a huge library of RNA-polymerases, which are currently used to generate mRNA from DNA templates during the manufacturing process.

They’ve also turned to E. coli to manufacture mRNA therapies more cheaply and hope to study how the sequence and structure of mRNA affects manufacturing yields.

“Even with all the money that’s gone into the development [of mRNA therapies], the cost remains high for standard dosing,” explains Adam Brown, PhD, an associate professor in biopharmaceutical engineering at the University of Sheffield.

Brown, who will be speaking at the BioProcess International Conference in Boston, believes that using a wider range of polymerases could help reduce manufacturing costs. His group took an engineering biology approach to identify forty polymerases that might be useful for manufacturing mRNA therapies. According to Brown, this is the largest library of single sub-unit polymerases in the world.

E. coli as an alternative to industry standard in IVT assays

The scientists are currently testing each polymerase in the laboratory to investigate how much mRNA it can produce during manufacturing. Previously, the team investigated using E. coli as an alternative to industry-standard in vitro transcription (IVT) assays for mRNA production.

The costs of using E. coli are an order of magnitude cheaper than IVT and the downstream processing of the mRNA product is not too complicated, notes Brown, adding that the original problem with using E. coli was it just chewed up mammalian mRNA, so we’ve used synthetic biology-based engineering to increase the yield–fifty-fold compared to using standard E. coli platforms.”

The researchers also tested the ease of purifying the final product by running it through a chromatography column.

“Clearly, the obvious downside of using E. coli is removing endotoxins and things like ribosomal RNA, but we’re getting large yields, easily, and large-scale E. coli production is something that can be done in any lab in the world,” points out Brown, who hopes his work will give mRNA therapy manufacturers a wider range of manufacturing options, as the industry develops, and the technology becomes more complex.

“At the moment mRNA [therapies] are quite simple, but they will inevitably become more complex, like proteins, with products like self-amplifying RNA and big circular molecules,” he says.

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