Branched chemically modified poly(A) tails enhance the translation capacity of mRNA

doi:10.1038/s41587-024-02174-7

. 2024 Mar 22.

doi: 10.1038/s41587-024-02174-7. Online ahead of print.

Branched chemically modified poly(A) tails enhance the translation capacity of mRNA

Hongyu Chen^{1

2}, Dangliang Liu^{1

2}, Jianting Guo^{1

2}, Abhishek Aditham^{2

3}, Yiming Zhou^{1

2

4}, Jiakun Tian^{1

2}, Shuchen Luo^{1

2}, Jingyi Ren^{1

2}, Alvin Hsu^{5

6

7}, Jiahao Huang^{1

2}, Franklin Kostas^{1

2}, Mingrui Wu^{1

2}, David R Liu^{5

6

7}, Xiao Wang^{8

9

10}

Affiliations

¹ Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
² Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA.
⁷ Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
⁸ Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA. xwangx@mit.edu.
⁹ Broad Institute of MIT and Harvard, Cambridge, MA, USA. xwangx@mit.edu.
¹⁰ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. xwangx@mit.edu.

PMID: 38519719
DOI: 10.1038/s41587-024-02174-7

Branched chemically modified poly(A) tails enhance the translation capacity of mRNA

Hongyu Chen et al. Nat Biotechnol. 2024.

. 2024 Mar 22.

doi: 10.1038/s41587-024-02174-7. Online ahead of print.

Authors

Affiliations

¹ Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA.
² Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Howard Hughes Medical Institute, Harvard University, Cambridge, MA, USA.
⁷ Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
⁸ Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA. xwangx@mit.edu.
⁹ Broad Institute of MIT and Harvard, Cambridge, MA, USA. xwangx@mit.edu.
¹⁰ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. xwangx@mit.edu.

PMID: 38519719
DOI: 10.1038/s41587-024-02174-7

Abstract

Although messenger RNA (mRNA) has proved effective as a vaccine, its potential as a general therapeutic modality is limited by its instability and low translation capacity. To increase the duration and level of protein expression from mRNA, we designed and synthesized topologically and chemically modified mRNAs with multiple synthetic poly(A) tails. Here we demonstrate that the optimized multitailed mRNA yielded ~4.7-19.5-fold higher luminescence signals than the control mRNA from 24 to 72 h post transfection in cellulo and 14 days detectable signal versus <7 days signal from the control in vivo. We further achieve efficient multiplexed genome editing of the clinically relevant genes Pcsk9 and Angptl3 in mouse liver at a minimal mRNA dosage. Taken together, these results provide a generalizable approach to synthesize capped branched mRNA with markedly enhanced translation capacity.

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References

1. Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics—developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014). - PubMed - DOI
1. Weng, Y. et al. The challenge and prospect of mRNA therapeutics landscape. Biotechnol. Adv. 40, 107534 (2020). - PubMed - DOI
1. Rohner, E., Yang, R., Foo, K. S., Goedel, A. & Chien, K. R. Unlocking the promise of mRNA therapeutics. Nat. Biotechnol. 40, 1586–1600 (2022). - PubMed - DOI
1. Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2021). - PubMed - DOI
1. Walsh, E. E. et al. Safety and immunogenicity of two RNA-based COVID-19 vaccine candidates. N. Engl. J. Med. 383, 2439–2450 (2020) - PubMed - DOI

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1DP2GM146245-01/U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)

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[1] Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics—developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014). - PubMed - DOI

[2] Sahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics—developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759–780 (2014). - PubMed - DOI

[3] Weng, Y. et al. The challenge and prospect of mRNA therapeutics landscape. Biotechnol. Adv. 40, 107534 (2020). - PubMed - DOI

[4] Weng, Y. et al. The challenge and prospect of mRNA therapeutics landscape. Biotechnol. Adv. 40, 107534 (2020). - PubMed - DOI

[5] Rohner, E., Yang, R., Foo, K. S., Goedel, A. & Chien, K. R. Unlocking the promise of mRNA therapeutics. Nat. Biotechnol. 40, 1586–1600 (2022). - PubMed - DOI

[6] Rohner, E., Yang, R., Foo, K. S., Goedel, A. & Chien, K. R. Unlocking the promise of mRNA therapeutics. Nat. Biotechnol. 40, 1586–1600 (2022). - PubMed - DOI

[7] Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2021). - PubMed - DOI

[8] Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2021). - PubMed - DOI

[9] Walsh, E. E. et al. Safety and immunogenicity of two RNA-based COVID-19 vaccine candidates. N. Engl. J. Med. 383, 2439–2450 (2020) - PubMed - DOI

[10] Walsh, E. E. et al. Safety and immunogenicity of two RNA-based COVID-19 vaccine candidates. N. Engl. J. Med. 383, 2439–2450 (2020) - PubMed - DOI

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Branched chemically modified poly(A) tails enhance the translation capacity of mRNA

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Branched chemically modified poly(A) tails enhance the translation capacity of mRNA

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