Therapeutic application of circular RNA aptamers in a mouse model of psoriasis

doi:10.1038/s41587-024-02204-4

. 2024 Apr 23.

doi: 10.1038/s41587-024-02204-4. Online ahead of print.

Therapeutic application of circular RNA aptamers in a mouse model of psoriasis

Si-Kun Guo^#¹, Chu-Xiao Liu^#¹, Yi-Feng Xu^#¹, Xiao Wang^#¹, Fang Nan^#², Youkui Huang¹, Siqi Li¹, Shan Nan¹, Ling Li^{1

3}, Edo Kon⁴, Chen Li¹, Meng-Yuan Wei¹, Rina Su⁵, Jia Wei², Shiguang Peng⁵, Nitay Ad-El⁴, Jiaquan Liu¹, Dan Peer⁴, Ting Chen⁶, Li Yang², Ling-Ling Chen^{7

8

9

10}

Affiliations

¹ Key Laboratory of RNA Innovation, Science and Engineering, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
² Center for Molecular Medicine, Children's Hospital of Fudan University and Shanghai Key Laboratory of Medical Epigenetics, International Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
³ School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
⁴ Laboratory of Precision Nanomedicine, Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Department of Materials Sciences and Engineering, Iby and Aladar Fleischman Faculty of Engineering, Center for Nanoscience and Nanotechnology, Cancer Biology Research Center, Tel Aviv University, Tel Aviv, Israel.
⁵ Department of Dermatology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China.
⁶ National Institute of Biological Sciences, Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China.
⁷ Key Laboratory of RNA Innovation, Science and Engineering, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. linglingchen@sibcb.ac.cn.
⁸ School of Life Science and Technology, ShanghaiTech University, Shanghai, China. linglingchen@sibcb.ac.cn.
⁹ New Cornerstone Science Laboratory, Shenzhen, China. linglingchen@sibcb.ac.cn.
¹⁰ Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. linglingchen@sibcb.ac.cn.

^# Contributed equally.

PMID: 38653797
DOI: 10.1038/s41587-024-02204-4

Therapeutic application of circular RNA aptamers in a mouse model of psoriasis

Si-Kun Guo et al. Nat Biotechnol. 2024.

. 2024 Apr 23.

doi: 10.1038/s41587-024-02204-4. Online ahead of print.

Authors

Affiliations

¹ Key Laboratory of RNA Innovation, Science and Engineering, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
² Center for Molecular Medicine, Children's Hospital of Fudan University and Shanghai Key Laboratory of Medical Epigenetics, International Laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
³ School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
⁴ Laboratory of Precision Nanomedicine, Shmunis School of Biomedicine and Cancer Research, George S. Wise Faculty of Life Sciences, Department of Materials Sciences and Engineering, Iby and Aladar Fleischman Faculty of Engineering, Center for Nanoscience and Nanotechnology, Cancer Biology Research Center, Tel Aviv University, Tel Aviv, Israel.
⁵ Department of Dermatology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China.
⁶ National Institute of Biological Sciences, Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China.
⁷ Key Laboratory of RNA Innovation, Science and Engineering, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. linglingchen@sibcb.ac.cn.
⁸ School of Life Science and Technology, ShanghaiTech University, Shanghai, China. linglingchen@sibcb.ac.cn.
⁹ New Cornerstone Science Laboratory, Shenzhen, China. linglingchen@sibcb.ac.cn.
¹⁰ Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. linglingchen@sibcb.ac.cn.

^# Contributed equally.

PMID: 38653797
DOI: 10.1038/s41587-024-02204-4

Abstract

Efforts to advance RNA aptamers as a new therapeutic modality have been limited by their susceptibility to degradation and immunogenicity. In a previous study, we demonstrated synthesized short double-stranded region-containing circular RNAs (ds-cRNAs) with minimal immunogenicity targeted to dsRNA-activated protein kinase R (PKR). Here we test the therapeutic potential of ds-cRNAs in a mouse model of imiquimod-induced psoriasis. We find that genetic supplementation of ds-cRNAs leads to inhibition of PKR, resulting in alleviation of downstream interferon-α and dsRNA signals and attenuation of psoriasis phenotypes. Delivery of ds-cRNAs by lipid nanoparticles to the spleen attenuates PKR activity in examined splenocytes, resulting in reduced epidermal thickness. These findings suggest that ds-cRNAs represent a promising approach to mitigate excessive PKR activation for therapeutic purposes.

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References

1. Hause, A. M. et al. Safety monitoring of bivalent COVID-19 mRNA vaccine booster doses among persons aged >/=12 years—United States, August 31-October 23, 2022. MMWR Morb. Mortal Wkly Rep. 71, 1401–1406 (2022). - PubMed - PMC - DOI
1. Winkle, M., El-Daly, S. M., Fabbri, M. & Calin, G. A. Noncoding RNA therapeutics—challenges and potential solutions. Nat Rev. Drug Discov. 20, 629–651 (2021). - PubMed - PMC - DOI
1. Enuka, Y. et al. Circular RNAs are long-lived and display only minimal early alterations in response to a growth factor. Nucleic Acids Res. 44, 1370–1383 (2016). - PubMed - DOI
1. Zhang, Y. et al. The biogenesis of nascent circular RNAs. Cell Rep. 15, 611–624 (2016). - PubMed - DOI
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[1] Hause, A. M. et al. Safety monitoring of bivalent COVID-19 mRNA vaccine booster doses among persons aged >/=12 years—United States, August 31-October 23, 2022. MMWR Morb. Mortal Wkly Rep. 71, 1401–1406 (2022). - PubMed - PMC - DOI

[2] Hause, A. M. et al. Safety monitoring of bivalent COVID-19 mRNA vaccine booster doses among persons aged >/=12 years—United States, August 31-October 23, 2022. MMWR Morb. Mortal Wkly Rep. 71, 1401–1406 (2022). - PubMed - PMC - DOI

[3] Winkle, M., El-Daly, S. M., Fabbri, M. & Calin, G. A. Noncoding RNA therapeutics—challenges and potential solutions. Nat Rev. Drug Discov. 20, 629–651 (2021). - PubMed - PMC - DOI

[4] Winkle, M., El-Daly, S. M., Fabbri, M. & Calin, G. A. Noncoding RNA therapeutics—challenges and potential solutions. Nat Rev. Drug Discov. 20, 629–651 (2021). - PubMed - PMC - DOI

[5] Enuka, Y. et al. Circular RNAs are long-lived and display only minimal early alterations in response to a growth factor. Nucleic Acids Res. 44, 1370–1383 (2016). - PubMed - DOI

[6] Enuka, Y. et al. Circular RNAs are long-lived and display only minimal early alterations in response to a growth factor. Nucleic Acids Res. 44, 1370–1383 (2016). - PubMed - DOI

[7] Zhang, Y. et al. The biogenesis of nascent circular RNAs. Cell Rep. 15, 611–624 (2016). - PubMed - DOI

[8] Zhang, Y. et al. The biogenesis of nascent circular RNAs. Cell Rep. 15, 611–624 (2016). - PubMed - DOI

[9] Fischer, J. W., Busa, V. F., Shao, Y. & Leung, A. K. L. Structure-mediated RNA decay by UPF1 and G3BP1. Mol. Cell. 78, 70–84.e76 (2020). - PubMed - PMC - DOI

[10] Fischer, J. W., Busa, V. F., Shao, Y. & Leung, A. K. L. Structure-mediated RNA decay by UPF1 and G3BP1. Mol. Cell. 78, 70–84.e76 (2020). - PubMed - PMC - DOI

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Therapeutic application of circular RNA aptamers in a mouse model of psoriasis

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Therapeutic application of circular RNA aptamers in a mouse model of psoriasis

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