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Purification of therapeutic & prophylactic mRNA by affinity chromatography

Grinsted, Julian; Liddell, John; Bouleghlimat, Emir; Kwok, Ka Yan; Taylor, Georgia; Marques, Marco PC; Bracewell, Daniel G; (2022) Purification of therapeutic & prophylactic mRNA by affinity chromatography. Cell and Gene Therapy Insights , 8 (2) pp. 335-349. 10.18609/cgti.2022.049. Green open access

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Abstract

In vitro transcribed mRNA is an emerging therapeutic and prophylactic modality with the potential to transform medicine. The drug platform features exceptionally rapid development and versatility of manufacturing processes. Despite the prompt advancement of mRNA from trials to market, purification challenges remain. The cell-free synthesis of mRNA is responsible for the generation of product and process-related impurities, creating the potential for immunogenic effects and decreased translatability into the clinic. Affinity chromatography presents itself as an effective primary capture step for the isolation of functional transcripts from product and some process related impurities. Developing platform processes for the affinity purification of mRNA is hindered by the varying strand lengths of non-amplifying, self-amplifying, and trans-amplifying constructs, with disparities in capacity being observed. Ligand chemistries may contribute to non-specific binding events which remain challenging to characterise. Improved elution and wash conditions may be pursued through novel ligand chemistries, enhanced density and spacing. Regardless of the size or application of the product, the impurities generated by in vitro transcription represent a significant obstacle to the safe administration and long-term storage of mRNA. Affinity chromatography is a valuable tool in overcoming these challenges, with current commercially available products relying heavily on oligo deoxythymidine ligand chemistries. Whilst affinity chromatography is highly valuable in the purification of mRNA, the inability to separate key secondary structures such as double-stranded RNA means it remains to be seen if this technology will adopt the same position as protein A does in mAb manufacture.

Type: Article
Title: Purification of therapeutic & prophylactic mRNA by affinity chromatography
Open access status: An open access version is available from UCL Discovery
DOI: 10.18609/cgti.2022.049
Publisher version: https://doi.org/10.18609/cgti.2022.049
Language: English
Additional information: Published by Cell and Gene Therapy Insights under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.
UCL classification: UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Biochemical Engineering
UCL > Provost and Vice Provost Offices > UCL BEAMS
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10151757
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