Versatile strategy using vaccinia virus-capping enzyme to synthesize functional 5′ cap-modified mRNAs

Ohno, Hirohisa; Akamine, Sae; Mochizuki, Megumi; Hayashi, Karin; Akichika, Shinichiro; Suzuki, Tsutomu; Saito, Hirohide

doi:10.1093/nar/gkad019

Cited by 12 publications

(6 citation statements)

References 49 publications

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“…This approach significantly improved translation efficiency and enhanced the functional properties of mRNA, making it a great potential candidate for use in therapeutic and biological research. 427 The addition of a 5′ cap and a 3′ poly(A) tail to mRNA vectors with 5′ and 3′ hairpins (haRh) significantly enhanced mRNA functionality as a vaccine or therapy. In another study, a VEGF-A mRNA structure was constructed that included a 5′ cap, VEGF-A, 3′-UTR, and poly(A) tail.…”

Section: Chemical Modifications On Mrnamentioning

confidence: 99%

“…In a recent study, a functional mRNA was synthesized using a simple and effective strategy that involved modifying various 5′ cap analogs. This approach significantly improved translation efficiency and enhanced the functional properties of mRNA, making it a great potential candidate for use in therapeutic and biological research . The addition of a 5′ cap and a 3′ poly(A) tail to mRNA vectors with 5′ and 3′ hairpins (haRh) significantly enhanced mRNA functionality as a vaccine or therapy.…”

Section: Chemical Modifications On Rna Molecules In Preclinical Researchmentioning

confidence: 99%

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Chemically Modified Platforms for Better RNA Therapeutics

Shi,

Zhen,

Zhang

et al. 2024

Chem. Rev.

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RNA-based therapies have catalyzed a revolutionary transformation in the biomedical landscape, offering unprecedented potential in disease prevention and treatment. However, despite their remarkable achievements, these therapies encounter substantial challenges including low stability, susceptibility to degradation by nucleases, and a prominent negative charge, thereby hindering further development. Chemically modified platforms have emerged as a strategic innovation, focusing on precise alterations either on the RNA moieties or their associated delivery vectors. This comprehensive review delves into these platforms, underscoring their significance in augmenting the performance and translational prospects of RNA-based therapeutics. It encompasses an in-depth analysis of various chemically modified delivery platforms that have been instrumental in propelling RNA therapeutics toward clinical utility. Moreover, the review scrutinizes the rationale behind diverse chemical modification techniques aiming at optimizing the therapeutic efficacy of RNA molecules, thereby facilitating robust disease management. Recent empirical studies corroborating the efficacy enhancement of RNA therapeutics through chemical modifications are highlighted. Conclusively, we offer profound insights into the transformative impact of chemical modifications on RNA drugs and delineates prospective trajectories for their future development and clinical integration. CONTENTS1. Introduction 930 2. Current Status and Challenges of RNA Therapeutics in Clinics 933 2.1. Molecular Mechanisms and Clinical Research Progress of RNAs 934 2.1.1. ASO 934 2.1.2. siRNA 934 2.1.3. Aptamer 936 2.1.4. mRNA 936 2.1.5. RNA Therapeutics on the Cusp of Clinical Breakthroughs 938 2.2. Major Challenges of Current RNA Therapeutics in Clinics 940 2.

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Section: Chemical Modifications On Mrnamentioning

confidence: 99%

Section: Chemical Modifications On Rna Molecules In Preclinical Researchmentioning

confidence: 99%

Chemically Modified Platforms for Better RNA Therapeutics

Shi,

Zhen,

Zhang

et al. 2024

Chem. Rev.

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“… 26 Recent advancements include the use of VCE to introduce GTP analogs at the 5’ end, creating modified mRNAs. 27 Moreover, Integrating T7 RNA polymerase with VCE simplifies cap-modified mRNA synthesis, reducing the need for expensive analogs. 28 Continuous cap analog optimization has significantly improved mRNA stability and transcription, enhancing its research and application potential ( Table 2 ).…”

Section: Rna-based Vectors For Antigen Expressionmentioning

confidence: 99%

Recent progress in mRNA cancer vaccines

Yao,

Xie,

Xia

2024

Human Vaccines & Immunotherapeutics

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The research and development of messenger RNA (mRNA) cancer vaccines have gradually overcome numerous challenges through the application of personalized cancer antigens, structural optimization of mRNA, and the development of alternative RNA-based vectors and efficient targeted delivery vectors. Clinical trials are currently underway for various cancer vaccines that encode tumor-associated antigens (TAAs), tumor-specific antigens (TSAs), or immunomodulators. In this paper, we summarize the optimization of mRNA and the emergence of RNA-based expression vectors in cancer vaccines. We begin by reviewing the advancement and utilization of state-of-the-art targeted lipid nanoparticles (LNPs), followed by presenting the primary classifications and clinical applications of mRNA cancer vaccines. Collectively, mRNA vaccines are emerging as a central focus in cancer immunotherapy, offering the potential to address multiple challenges in cancer treatment, either as standalone therapies or in combination with current cancer treatments.

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“…The most evident difference between the two methods is access to mRNA with chemically modified caps. Although some GTP analogs are tolerated by the vaccinia enzyme as substrates for GMP transfer, the co-transcriptional capping with trinucleotides offers a more general platform for incorporating modifications. Those include natural methylations of 5′-terminal nucleotides (cap-1, cap-2, m 6 A m ), ,, noncanonical caps, synthetic modulators of translational properties, , and functional groups for molecular labeling. − …”

Section: How To Cap Rnamentioning

confidence: 99%

Chemical Modifications of mRNA Ends for Therapeutic Applications

Warminski,

Mamot,

Depaix

et al. 2023

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations CONSPECTUS: Messenger ribonucleic acid (mRNA) is the universal cellular instruction for ribosomes to produce proteins. Proteins are responsible for most of the functions of living organisms, and their abnormal structure or activity is the cause of many diseases. mRNA, which is expressed in the cytoplasm and, unlike DNA, does not need to be delivered into the nucleus, appears to be an ideal vehicle for pursuing the idea of gene therapy in which genetic information about proteins is introduced into an organism to exert a therapeutic effect. mRNA molecules of any sequence can be synthesized using the same set of reagents in a cell-free system via a process called in vitro transcription (IVT), which is very convenient for therapeutic applications. However, this does not mean that the path from the idea to the first mRNA-based therapeutic was short and easy. It took 30 years of trial and error in the search for solutions that eventually led to the first mRNA vaccines created in record time during the SARS-CoV-2 pandemic. One of the fundamental problems in the development of RNA-based therapeutics is the legendary instability of mRNA, due to the transient nature of this macromolecule. From the chemical point of view, mRNA is a linear biopolymer composed of four types of ribonucleic subunits ranging in length from a few hundred to hundreds of thousands of nucleotides, with unique structures at its ends: a 5′-cap at the 5′-end and a poly(A) tail at the 3′-end. Both are extremely important for the regulation of translation and mRNA durability. These elements are also convenient sites for sequence-independent labeling of mRNA to create probes for enzymatic assays and tracking of the fate of mRNA in cells and living organisms. Synthetic 5′-cap analogs have played an important role in the studies of mRNA metabolism, and some of them have also been shown to significantly improve the translational properties of mRNA or affect mRNA stability and reactogenicity. The most effective of these is used in clinical trials of mRNA-based anticancer vaccines. Interestingly, thanks to the knowledge gained from the biophysical studies of cap-related processes, even relatively large modifications such as fluorescent tags can be attached to the cap structure without significant effects on the biological properties of the mRNA, if properly designed cap analogs are used. This has been exploited in the development of molecular tools (fluorescently labeled mRNAs) to track these macromolecules in complex biological systems, including organisms. These tools are extremely valuable for better understanding of the cellular mechanisms involved in mRNA metabolism but also for designing therapeutic mRNAs with superior properties. Much less is known about the usefulness/utility of poly(A) tail modifications in the therapeutic context, but it is clear that chemical modifications of poly(A) can also affect biochemical properties of mRNA. This Account is devoted to chemical modifications of both the 5′-and 3′-ends of mR...

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Versatile strategy using vaccinia virus-capping enzyme to synthesize functional 5′ cap-modified mRNAs

Cited by 12 publications

References 49 publications

Chemically Modified Platforms for Better RNA Therapeutics

Chemically Modified Platforms for Better RNA Therapeutics

Recent progress in mRNA cancer vaccines

Chemical Modifications of mRNA Ends for Therapeutic Applications

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