Advanced search
1 file | 1.53 MB Add to list

Corticosteroids and cellulose purification improve, respectively, the in vivo translation and vaccination efficacy of sa-mRNAs

(2021) MOLECULAR THERAPY. 29(4). p.1370-1381
Author
Organization
Abstract
Synthetic mRNAs are an appealing platform with multiple biomedical applications ranging from protein replacement therapy to vaccination. In comparison with conventional mRNA, synthetic self-amplifying mRNAs (sa-mRNAs) are gaining interest because of their higher and longer-lasting expression. However, sa-mRNAs also elicit an innate immune response, which may complicate their clinical application. Approaches to reduce the innate immunity of sa-mRNAs have not been studied in detail. Here we investigated, in vivo, the effect of several innate immune inhibitors and a novel cellulose-based mRNA purification approach on the type I interferon (IFN) response and the translation and vaccination efficacy of our formerly developed sa-mRNA vaccine against Zika virus. Among the investigated inhibitors, we found that corticosteroids and especially topical application of clobetasol at the sa-mRNA injection site was the most efficient in suppressing the type I IFN response and increasing the translation of sa-mRNA. However, clobetasol prevented formation of antibodies against sa-mRNA-encoded antigens and should therefore be avoided in a vaccination context. Residual dsRNA by-products of the in vitro transcription reaction are known inducers of immediate type I IFN responses. We additionally demonstrate a drastic reduction of these dsRNA by-products upon cellulose-based purification, reducing the innate immune response and improving sa-mRNA vaccination efficacy.
Keywords
Molecular Medicine, Genetics, Molecular Biology, Pharmacology, Drug Discovery, Zika vaccine, cellulose, clobetasol, innate immunity inhibitors, mRNA purification, self-amplifying mRNA, type I IFN

Downloads

  • (...).pdf
    • full text (Published version)
    • |
    • UGent only
    • |
    • PDF
    • |
    • 1.53 MB

Citation

Please use this url to cite or link to this publication:

MLA
Zhong, Zifu, et al. “Corticosteroids and Cellulose Purification Improve, Respectively, the in Vivo Translation and Vaccination Efficacy of Sa-MRNAs.” MOLECULAR THERAPY, vol. 29, no. 4, 2021, pp. 1370–81, doi:10.1016/j.ymthe.2021.01.023.
APA
Zhong, Z., Mc Cafferty, S., Opsomer, L., Wang, H., Huysmans, H., De Temmerman, J., … Sanders, N. (2021). Corticosteroids and cellulose purification improve, respectively, the in vivo translation and vaccination efficacy of sa-mRNAs. MOLECULAR THERAPY, 29(4), 1370–1381. https://doi.org/10.1016/j.ymthe.2021.01.023
Chicago author-date
Zhong, Zifu, Séan Mc Cafferty, Lisa Opsomer, Haixiu Wang, Hanne Huysmans, Joyca De Temmerman, Stefan Lienenklaus, João Portela Catani, Francis Combes, and Niek Sanders. 2021. “Corticosteroids and Cellulose Purification Improve, Respectively, the in Vivo Translation and Vaccination Efficacy of Sa-MRNAs.” MOLECULAR THERAPY 29 (4): 1370–81. https://doi.org/10.1016/j.ymthe.2021.01.023.
Chicago author-date (all authors)
Zhong, Zifu, Séan Mc Cafferty, Lisa Opsomer, Haixiu Wang, Hanne Huysmans, Joyca De Temmerman, Stefan Lienenklaus, João Portela Catani, Francis Combes, and Niek Sanders. 2021. “Corticosteroids and Cellulose Purification Improve, Respectively, the in Vivo Translation and Vaccination Efficacy of Sa-MRNAs.” MOLECULAR THERAPY 29 (4): 1370–1381. doi:10.1016/j.ymthe.2021.01.023.
Vancouver
1.
Zhong Z, Mc Cafferty S, Opsomer L, Wang H, Huysmans H, De Temmerman J, et al. Corticosteroids and cellulose purification improve, respectively, the in vivo translation and vaccination efficacy of sa-mRNAs. MOLECULAR THERAPY. 2021;29(4):1370–81.
IEEE
[1]
Z. Zhong et al., “Corticosteroids and cellulose purification improve, respectively, the in vivo translation and vaccination efficacy of sa-mRNAs,” MOLECULAR THERAPY, vol. 29, no. 4, pp. 1370–1381, 2021.
@article{8702821,
  abstract     = {{Synthetic mRNAs are an appealing platform with multiple biomedical applications ranging from protein replacement therapy to vaccination. In comparison with conventional mRNA, synthetic self-amplifying mRNAs (sa-mRNAs) are gaining interest because of their higher and longer-lasting expression. However, sa-mRNAs also elicit an innate immune response, which may complicate their clinical application. Approaches to reduce the innate immunity of sa-mRNAs have not been studied in detail. Here we investigated, in vivo, the effect of several innate immune inhibitors and a novel cellulose-based mRNA purification approach on the type I interferon (IFN) response and the translation and vaccination efficacy of our formerly developed sa-mRNA vaccine against Zika virus. Among the investigated inhibitors, we found that corticosteroids and especially topical application of clobetasol at the sa-mRNA injection site was the most efficient in suppressing the type I IFN response and increasing the translation of sa-mRNA. However, clobetasol prevented formation of antibodies against sa-mRNA-encoded antigens and should therefore be avoided in a vaccination context. Residual dsRNA by-products of the in vitro transcription reaction are known inducers of immediate type I IFN responses. We additionally demonstrate a drastic reduction of these dsRNA by-products upon cellulose-based purification, reducing the innate immune response and improving sa-mRNA vaccination efficacy.}},
  author       = {{Zhong, Zifu and Mc Cafferty, Séan and Opsomer, Lisa and Wang, Haixiu and Huysmans, Hanne and De Temmerman, Joyca and Lienenklaus, Stefan and Portela Catani, João and Combes, Francis and Sanders, Niek}},
  issn         = {{1525-0016}},
  journal      = {{MOLECULAR THERAPY}},
  keywords     = {{Molecular Medicine,Genetics,Molecular Biology,Pharmacology,Drug Discovery,Zika vaccine,cellulose,clobetasol,innate immunity inhibitors,mRNA purification,self-amplifying mRNA,type I IFN}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{1370--1381}},
  title        = {{Corticosteroids and cellulose purification improve, respectively, the in vivo translation and vaccination efficacy of sa-mRNAs}},
  url          = {{http://dx.doi.org/10.1016/j.ymthe.2021.01.023}},
  volume       = {{29}},
  year         = {{2021}},
}

Altmetric
View in Altmetric
Web of Science
Times cited: