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

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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.CC BY-NC-ND · PubMed Central

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.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.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.CC BY-NC-ND · PubMed Central

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Authors: Youn, H., & Chung, J.-K.
Affiliations: Seoul National University (KR)
Corresponding author: Chung, June-Key
ORCID: Youn, Hyewon
Chung, June-Key
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: hybrid
doi.org
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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Modified mRNA as an alternative to plasmid DNA (pDNA) for transcript replacement and vaccination therapy

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