Nair, A. orcid.org/0000-0002-2592-116X and Kis, Z. (2024) Bacteriophage RNA polymerases: catalysts for mRNA vaccines and therapeutics. Frontiers in Molecular Biosciences, 11. 1504876. ISSN 2296-889X
Abstract
Decades of research on bacteriophage-derived RNA polymerases (RNAPs) were vital for synthesizing mRNA using the in vitro transcription (IVT) reaction for vaccines during the COVID-19 pandemic. The future success of mRNA-based products relies on the efficiency of its manufacturing process. mRNA manufacturing is a platform technology that complements the quality by design (QbD) paradigm. We applied the QbD framework in combination with key mechanistic insights on RNAP to assess the impact of IVT-associated critical process parameters (CPPs) and critical material attributes (CMAs) on the critical quality attributes (CQAs) of the mRNA drug substance and on manufacturing key performance indicators (KPIs). We also summarize the structure-function relationship of T7 RNAP and its engineered mutants aimed at enhancing the critical production of low-immunogenic mRNA therapeutics. Alternatives to the current set of standard RNAPs in large-scale IVTs are also discussed based on a phylogenetic background. Finally, the review dives into the economic implications of improving mRNA manufacturing based on the main enzyme, T7 RNAP, used to synthesize the mRNA drug substance. The review concludes by mapping the relationship between various CMAs and CPPs with different phases of the IVT reaction from a QbD perspective.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2024 Nair and Kis. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
Keywords: | bacteriophage RNA polymerase; T7 RNA polymerase; T7 RNA polymerase mutants; RNA polymerase engineering; in vitro transcription; mRNA vaccines and therapeutics; mRNA manufacturing; quality by design |
Dates: |
|
Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Engineering (Sheffield) > School of Chemical, Materials and Biological Engineering |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 13 Dec 2024 14:53 |
Last Modified: | 13 Dec 2024 14:53 |
Status: | Published |
Publisher: | Frontiers Media SA |
Refereed: | Yes |
Identification Number: | 10.3389/fmolb.2024.1504876 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:220366 |