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

Youn H, Chung JK - Expert Opin Biol Ther (2015)

Bottom Line: Conversely, gene delivery using plasmid DNA (pDNA) is considered safer, but its transfection efficiency is much lower than virus-mediated gene transfer.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.

View Article: PubMed Central - PubMed

Affiliation: Seoul National University, College of Medicine, Department of Nuclear Medicine , 103 Daehak-ro, Jongno-gu, Seoul 110-799 , Korea +82 2 2072 3341 ; +82 2 745 7690 ; jkchung@snu.ac.kr.

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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Related in: MedlinePlus

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.
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Figure 0001: 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.

Mentions: The main reason for mRNA instability is the presence of a hydroxyl group on the second carbon atom of the sugar moiety, which facilitates hydrolytic degradation. Either cis-acting or trans-acting factors can influence mRNA degradation [10]. 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) (Figure 1A).


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

Youn H, Chung JK - Expert Opin Biol Ther (2015)

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.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4696419&req=5

Figure 0001: 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.
Mentions: The main reason for mRNA instability is the presence of a hydroxyl group on the second carbon atom of the sugar moiety, which facilitates hydrolytic degradation. Either cis-acting or trans-acting factors can influence mRNA degradation [10]. 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) (Figure 1A).

Bottom Line: Conversely, gene delivery using plasmid DNA (pDNA) is considered safer, but its transfection efficiency is much lower than virus-mediated gene transfer.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.

View Article: PubMed Central - PubMed

Affiliation: Seoul National University, College of Medicine, Department of Nuclear Medicine , 103 Daehak-ro, Jongno-gu, Seoul 110-799 , Korea +82 2 2072 3341 ; +82 2 745 7690 ; jkchung@snu.ac.kr.

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.

Show MeSH
Related in: MedlinePlus