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  • Engineering Enhanced mRNA Structures for Next-Generation Therapeutics

    Messenger RNA (mRNA) technology, previously spotlighted for its pivotal role in COVID-19 vaccine development, is now spreading into other therapeutic territories, according to a recent study published in Nature Biotechnology. Researchers from the Broad Institute and MIT have introduced an innovative mRNA structure that enhances the molecule's stability and efficacy, potentially leading the way for treatments involving gene editing and protein replacement.

    Enhanced mRNA Structures for Therapeutic Use
    The study showcases the development of mRNA molecules adorned with multiple polyadenine (poly(A)) tails, a modification that has significantly increased the molecule's activity within cells by 5 to 20-fold. More strikingly, these multi-tailed mRNAs demonstrate a 2 to 3-fold increase in longevity in animal models compared to their unmodified counterparts. This enhanced durability and efficiency are crucial for diseases requiring long-term treatment approaches.

    Xiao Wang, the senior author and a core institute member at the Broad as well as an assistant professor of chemistry at MIT, expressed his enthusiasm for the project, stating, "The use of mRNA in COVID vaccines is fantastic, which prompted us to explore how we could expand the possible therapeutic applications for mRNA." Wang further emphasized the superiority of these engineered non-natural structures over naturally occurring ones.

    Advancing mRNA Therapeutics
    The researchers leveraged the multi-tailed mRNA within a CRISPR gene-editing framework, demonstrating more effective gene editing in mice. Specifically, they encoded the DNA-cutting Cas9 protein within their multi-tailed mRNA, achieving notable reductions in cholesterol levels through targeted gene editing of Pcsk9 and Angptl3 genes. This outcome underscores the potential of multi-tailed mRNA in gene therapy, particularly for conditions necessitating precise genetic modifications.

    Hongyu Chen, the paper's first author and a graduate student from MIT Chemistry in Wang's lab, highlighted the cellular machinery's compatibility with the new mRNA structure, opening doors to further synthetic modifications that could extend mRNA's therapeutic applications.

    Staying Power and Safety
    One of the pivotal challenges addressed by this research is the balance between mRNA's efficacy and safety. Traditional mRNA, while effective in small doses for vaccines, requires larger quantities for therapeutic applications, potentially leading to toxic side effects. The team's multi-tailed mRNAs aim to mitigate this by enhancing the molecule's stability and activity, thereby reducing the required dosage for therapeutic effects.

    The innovative approach to mRNA design involves not only the addition of multiple tails but also chemical modifications to the poly(A) tail, a strategy previously shown by Wang and Chen to slow mRNA degradation. This research builds on the concept of "mRNA-oligo conjugates" or mocRNAs, which the team introduced in prior work.

    This research marks a significant step forward in the quest to harness mRNA's full therapeutic potential, offering hope for the treatment of a wide range of diseases through gene editing and protein replacement strategies.

    Original Publication
    Chen, H., Liu, D., Guo, J. et al. Branched chemically modified poly(A) tails enhance the translation capacity of mRNA. Nat Biotechnol (2024). https://doi.org/10.1038/s41587-024-02174-7

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