Effects of Chemically Modified Messenger RNA on Protein Expression

Li, Bin; Luo, Xiao; Dong, Yizhou

doi:10.1021/acs.bioconjchem.6b00090

Cited by 115 publications

(102 citation statements)

References 21 publications

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“…Alternatively, mRNAs with a complete substitution of the unmodified nucleotide by a modified version were applied 71 . Thus, in order to obtain a more detailed picture of the direct effect of single mRNA modifications on protein synthesis, a refined systematic approach was applied.…”

Section: Translational Regulation Mediated By Mrna Modificationsmentioning

confidence: 99%

mRNA modifications: Dynamic regulators of gene expression?

2016

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The expression of a gene is a tightly regulated process and is exerted by a myriad of different mechanisms. Recently, RNA modifications located in coding sequences of mRNAs, have been identified as potential regulators of gene expression. N6-methyladenosine (m6A), 5-methylcytosine (m5C), pseudouridine (Ψ) and N1-methyladenosine (m1A) have been found within open reading frames of mRNAs. The presence of these mRNA modifications has been implicated to modulate the fate of an mRNA, ranging from maturation to its translation and even degradation. However, many aspects concerning the biological functions of mRNA modifications remain elusive. Recently, systematic in vitro studies allowed a first glimpse of the direct interplay of mRNA modifications and the efficiency and fidelity of ribosomal translation. It thereby became evident that the effects of mRNA modifications were, astonishingly versatile, depending on the type, position or sequence context. The incorporation of a single modification could either prematurely terminate protein synthesis, reduce the peptide yield or alter the amino acid sequence identity. These results implicate that mRNA modifications are a powerful mechanism to post-transcriptionally regulate gene expression.

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Section: Translational Regulation Mediated By Mrna Modificationsmentioning

confidence: 99%

mRNA modifications: Dynamic regulators of gene expression?

2016

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“…RNAs can be modified by means of chemical alterations to the ribose sugar (of particular importance is the 2′ position [45, 46]), the phosphate linkage and the individual bases (Fig. 1d) [47–50]. RNAs delivered through nanoparticles, discussed later, are also typically modified in order to avoid recognition by endosomally expressed pattern recognition receptors [51].…”

Section: Delivery Materials and Chemical Modifications For Rnamentioning

confidence: 99%

Advances in the delivery of RNA therapeutics: from concept to clinical reality

2017

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The rapid expansion of the available genomic data continues to greatly impact biomedical science and medicine. Fulfilling the clinical potential of genetic discoveries requires the development of therapeutics that can specifically modulate the expression of disease-relevant genes. RNA-based drugs, including short interfering RNAs and antisense oligonucleotides, are particularly promising examples of this newer class of biologics. For over two decades, researchers have been trying to overcome major challenges for utilizing such RNAs in a therapeutic context, including intracellular delivery, stability, and immune response activation. This research is finally beginning to bear fruit as the first RNA drugs gain FDA approval and more advance to the final phases of clinical trials. Furthermore, the recent advent of CRISPR, an RNA-guided gene-editing technology, as well as new strides in the delivery of messenger RNA transcribed in vitro, have triggered a major expansion of the RNA-therapeutics field. In this review, we discuss the challenges for clinical translation of RNA-based therapeutics, with an emphasis on recent advances in delivery technologies, and present an overview of the applications of RNA-based drugs for modulation of gene/protein expression and genome editing that are currently being investigated both in the laboratory as well as in the clinic.

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“…They include N 6 -methyladenosine (m 6 A), N 1 -methyladenosine (m 1 A), 2-thiouridine (s2U), 5-methyluridine (m5U), 5-methoxyuridine (mo5U), N 1 -methylpseudouridine (m 1 ψ), 5-methylcytidine (m5C), 5-hydroxymethylcytidine (hm5C), 5-methoxycytidine (mo5C), and 2-methylguanosine (m2G) [9, 74]. A recent study identified m 1 ψ, mo5U, and ψ as the top three favorable nucleosides for mRNA modification, which significantly augmented protein expression [75]. In addition, combining ψ and m5C in modified mRNA can produce higher protein expression compared to a single modification [76, 77].…”

Section: Chemical Modification Of Mrnamentioning

confidence: 99%

Biomedical applications of mRNA nanomedicine

et al. 2018

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As an attractive alternative to plasmid DNA, messenger RNA (mRNA) has recently emerged as a promising class of nucleic acid therapeutics for biomedical applications. Advances in addressing the inherent shortcomings of mRNA and in the development of nanoparticle-based delivery systems have prompted the development and clinical translation of mRNA-based medicines. In this review, we discuss the chemical modification strategies of mRNA to improve its stability, minimize immune responses, and enhance translational efficacy. We also highlight recent progress in nanoparticle-based mRNA delivery. Considerable attention is given to the increasingly widespread applications of mRNA nanomedicine in the biomedical fields of vaccination, protein-replacement therapy, gene editing, and cellular reprogramming and engineering.

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Effects of Chemically Modified Messenger RNA on Protein Expression

Cited by 115 publications

References 21 publications

mRNA modifications: Dynamic regulators of gene expression?

mRNA modifications: Dynamic regulators of gene expression?

Advances in the delivery of RNA therapeutics: from concept to clinical reality

Biomedical applications of mRNA nanomedicine

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