mRNA-based therapeutics — developing a new class of drugs

@article{ahin2014mRNAbasedT,
  title={mRNA-based therapeutics — developing a new class of drugs},
  author={Uğur Şahin and Katalin Karik{\'o} and {\"O}zlem T{\"u}reci},
  journal={Nature Reviews Drug Discovery},
  year={2014},
  volume={13},
  pages={759-780}
}
In vitro transcribed (IVT) mRNA has recently come into focus as a potential new drug class to deliver genetic information. Such synthetic mRNA can be engineered to transiently express proteins by structurally resembling natural mRNA. Advances in addressing the inherent challenges of this drug class, particularly related to controlling the translational efficacy and immunogenicity of the IVTmRNA, provide the basis for a broad range of potential applications. mRNA-based cancer immunotherapies and… 
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References

SHOWING 1-10 OF 260 REFERENCES
A development that may evolve into a revolution in medicine: mRNA as the basis for novel, nucleotide-based vaccines and drugs
Recent advances strongly suggest that mRNA rather than DNA will be the nucleotide basis for a new class of vaccines and drugs. Therapeutic cancer vaccines against a variety of targets have been…
Antitumor vaccination with synthetic mRNA: strategies for in vitro and in vivo preclinical studies.
TLDR
This chapter summarizes the state-of-art in this field and describes methods elementary for preclinical studies of mRNA-based antitumor vaccine protocols.
Tumor vaccination using messenger RNA: prospects of a future therapy.
Expression of therapeutic proteins after delivery of chemically modified mRNA in mice
TLDR
In a mouse model of a lethal congenital lung disease caused by a lack of surfactant protein B (SP-B), twice weekly local application of an aerosol of modified SP-B mRNA to the lung restored 71% of the wild-type SP- B expression, and treated mice survived until the predetermined end of the study after 28 days.
Systemic delivery of modified mRNA encoding herpes simplex virus 1 thymidine kinase for targeted cancer gene therapy.
TLDR
Modified mRNA encoding herpes simplex virus 1-thymidine kinase (HSV1-tk) was systemically delivered to H460 xenograft-bearing nude mice, it was significantly more effective in suppressing tumor growth than pDNA.
Phosphorothioate cap analogs increase stability and translational efficiency of RNA vaccines in immature dendritic cells and induce superior immune responses in vivo
TLDR
5′ mRNA cap analogs are established as yet another module for tuning immunopharmacological properties of recombinant antigen-encoding RNA for vaccination purposes by analyzing the effect of different synthetic 5′ mRNAcap analogs on the kinetics of the encoded protein.
RNAi-based therapeutic strategies for metabolic disease
TLDR
Lipid-based carriers of siRNA therapeutics can now target the liver in metabolic diseases and are being assessed in clinical trials for the treatment of hypercholesterolemia.
Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells.
TLDR
While investigating the impact of different structural modifications of RNA molecules on the kinetics of the encoded protein in DCs, components located 3' of the coding region that contributed to a higher transcript stability and translational efficiency were identified.
Vaccination with messenger RNA (mRNA).
  • S. Pascolo
  • Biology
    Handbook of experimental pharmacology
  • 2008
TLDR
The structure of mRNA, its possible optimizations for immunization purposes, the different methods of delivery used in preclinical studies, and finally the results of clinical trial where mRNA is the active pharmaceutical ingredient of new innovative vaccines are described.
RNA: the new revolution in nucleic acid vaccines.
...
...