Hung Trinh: Enhancing Therapeutic Messenger RNA Through Circularization
Hung Trinh, CMC/MFG Consultant and Managing Director at Vertex Biopharm Consulting, shared a post on LinkedIn:
“Chemical circularization of in vitro transcribed RNA for exploring circular mRNA design
Circularization is an important step for therapeutic messenger RNA (mRNA) enhancements. Current enzymatic and ribozymatic-based circularization methods face limitations including sequence constraints, purification challenges, and sub-optimal biological activity. Chemical strategies, while promising, have been restricted to short RNA sequences.
Here, we report a method for chemically circularized in vitro transcribed RNAs of various lengths (chem-circRNAs; 35–4000 nt) with circularization efficiencies reaching up to 60%. This approach leverages a 5′ ethylenediamine modification and a periodate-oxidized 3′ end to drive intramolecular reductive amination.
We demonstrate that this method is applicable to various sequences and modification compatible. We report the effective separation methods of chem-circRNAs from their linear precursors. We show that protein-coding chem-circRNAs are translationally active in cells and exhibit increased durability, like enzymatically circularized mRNAs.
Furthermore, our method allows incorporation of functional modifications, including endocyclic N7-methylguanosine cap and N1-methylpseudouridine, enabling access to chemically defined translationally active circRNAs for therapeutic applications.”
Title: Chemical circularization of in vitro transcribed RNA for exploring circular mRNA design
Authors: Malgorzata Wasinska-Kalwa, Adam Mamot, Karol Czubak, Katarzyna Frankowska, Adam Ado Rajkiewicz, Tomasz Spiewla, Marcin Warminski, Zofia Pilch, Marta Szulc-Gasiorowska, Kacper Siekan, Andrzej Dziembowski, Dominika Nowis, Jakub Golab, Joanna Kowalska, Jacek Jemielity
Read the Full Article on Nature Communications.
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