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Cited by 114RNA Interference and Gene DeliveryVirus-based gene therapy researchImmunotherapy and Immune Responses

The DOI matches its Crossref record; 74 of the 74 references it cites were found in a registry or an index.

Modified mRNA as an alternative to plasmid DNA (pDNA) for transcript replacement and vaccination therapy

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Youn, Hyewon, Chung, June-Key·2015·Expert Opinion on Biological Therapy
DOI 10.1517/14712598.2015.1057563PMC PMC4696419
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Abstract

INTRODUCTION: Current gene therapy involves replacement of defective gene by delivery of healthy genetic material to precede normal function. Virus-mediated gene delivery is the most successful and efficient method for gene therapy, but it has been challenged due to serious safety concerns. Conversely, gene delivery using plasmid DNA (pDNA) is considered safer, but its transfection efficiency is much lower than virus-mediated gene transfer. Recently, mRNA has been suggested as an alternative option to avoid undesired insertion of delivered DNA sequences with higher transfection efficiency and stability. AREA COVERED: In this review, we summarize the currently available strategies of mRNA modification to increase the therapeutic efficacy; we also highlight the recent improvements of mRNA delivery for in vivo applications of gene therapy. EXPERT OPINION: The use of mRNA-based gene transfer could indeed be a promising new strategy for gene therapy. Notable advantages include no risk of integration into the genomic DNA, adjustable gene expression and easier modulation of the immune system. By reducing or utilizing the immunogenic properties, mRNA offers a promising tool for gene/or transcript replacement.

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Figure 1. Typical gene deliveries for therapeutic application. A. pDNA or mRNA-mediated gene transfer is illustrated. pDNA contains the multiple cloning site (MCS), which is used for restriction endonuclease recognition to insert transgene. Mature eukaryotic mRNA consists of five significant portions, including the cap structure ([m7GpppN or m7Gp3N (N: any nucleotide)], the 5’ untranslated region (5’UTR), an open reading frame (ORF), the 3’ untranslated region (3’UTR) and a tail of 100 – 250 adenosine residues (Poly(A) tails). B. Regions of mRNA modifications for increasing their stability. C. Chemical structure of mRNA CAP. D. Standard dinucleotide cap analog. E. Anti-reverse cap analogs (ARCA). F. mRNA degradation pathways. Both major pathways of mRNA decay are initiated by deadenylation.
Figure 1. Typical gene deliveries for therapeutic application. A. pDNA or mRNA-mediated gene transfer is illustrated. pDNA contains the multiple cloning site (MCS), which is used for restriction endonuclease recognition to insert transgene. Mature eukaryotic mRNA consists of five significant portions, including the cap structure ([m7GpppN or m7Gp3N (N: any nucleotide)], the 5’ untranslated region (5’UTR), an open reading frame (ORF), the 3’ untranslated region (3’UTR) and a tail of 100 – 250 adenosine residues (Poly(A) tails). B. Regions of mRNA modifications for increasing their stability. C. Chemical structure of mRNA CAP. D. Standard dinucleotide cap analog. E. Anti-reverse cap analogs (ARCA). F. mRNA degradation pathways. Both major pathways of mRNA decay are initiated by deadenylation.CC BY-NC-ND · PubMed Central
Figure 2. Nucleoside modification of mRNA for immune escape.
Figure 2. Nucleoside modification of mRNA for immune escape.CC BY-NC-ND · PubMed Central
Figure 3. Different injection routes of gene delivery are outlined.
Figure 3. Different injection routes of gene delivery are outlined.CC BY-NC-ND · PubMed Central
Figure 4. Systemic delivery of modified mRNA for gene therapy. A. Diagram of formulating modified mRNA into a liposome-protamine-RNA (LPR) complex. B. Proliferation capacity of the surviving H460 cells after HSV-tk/GCV therapy, determined by clonogenic assay. C. Tumor growth inhibition of H460 non-small cell lung cancer after HSV-tk/GCV therapy by systemic delivery of modified mRNA in the LPR.
Figure 4. Systemic delivery of modified mRNA for gene therapy. A. Diagram of formulating modified mRNA into a liposome-protamine-RNA (LPR) complex. B. Proliferation capacity of the surviving H460 cells after HSV-tk/GCV therapy, determined by clonogenic assay. C. Tumor growth inhibition of H460 non-small cell lung cancer after HSV-tk/GCV therapy by systemic delivery of modified mRNA in the LPR.CC BY-NC-ND · PubMed Central
Figure 5. Evaluating in vivo transfection efficiency of naked or nanoparticle-based modified (ARCA) mRNA according to the administration routes. A. Bioluminescence in C57BL/6 mice transfected intranasally with 4 μg of p/mLuc and n/mLuc over a 4-h time period. B. Bioluminescence in C57BL/6 mice transfected subcutaneously at the base of the ear pinna with p/mLuc and n/mLuc (in NaAc and RL) at 4 h. C. Bioluminescence signal in BALB/c mice intravenously administrated with 26 μg of p/mLuc and m/Luc at 8 h time points with respective color scales.
Figure 5. Evaluating in vivo transfection efficiency of naked or nanoparticle-based modified (ARCA) mRNA according to the administration routes. A. Bioluminescence in C57BL/6 mice transfected intranasally with 4 μg of p/mLuc and n/mLuc over a 4-h time period. B. Bioluminescence in C57BL/6 mice transfected subcutaneously at the base of the ear pinna with p/mLuc and n/mLuc (in NaAc and RL) at 4 h. C. Bioluminescence signal in BALB/c mice intravenously administrated with 26 μg of p/mLuc and m/Luc at 8 h time points with respective color scales.CC BY-NC-ND · PubMed Central

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Metadata

Authors
Youn, H., & Chung, J.-K.
Affiliations
Seoul National University (KR)
Corresponding author
Chung, June-Key
ORCID
Venue
Expert Opinion on Biological Therapy
Publisher
Informa UK Limited
Published
2015-06-30
Volume
15
Issue
9
Pages
1337-1348
ISSN
  • 1471-2598 (ISSN-L)
  • 1744-7682
DOI
10.1517/14712598.2015.1057563
PMC
PMC4696419
OpenAlex
W1667670121
Cited by
114
References
73
Citations by year
2026: 11 · 2025: 11 · 2024: 8 · 2023: 17 · 2022: 12 · 2021: 10 · 2020: 8 · 2019: 14 · 2018: 10 · 2017: 7 · 2016: 6
FWCI
0.74
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Expert Opinion on Biological Therapy (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Deutsches Krebsforschungszentrum
  • National Research Foundation (2011-0030001)
  • Seoul National University (2011-0030001)
  • Ministry of Science, ICT and Future Planning (2011‐0030001)
  • Korea Health Industry Development Institute (HI14C1072, HI13C0826)
  • National Research Foundation of Korea (2011‐0030001, HI14C1072)
  • Seoul National University Hospital
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords
mRNA modification, plasmid DNA, gene therapy, therapeutic vaccination, mRNA delivery, transfection efficiency, immunogenicity, in vivo gene therapy
MeSH terms
Animals, Humans, Nucleosides, Plasmids, RNA Caps, RNA, Messenger, Transfection, Vaccination, Genetic Therapy, Immunotherapy, Active, Untranslated Regions

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