An overview of rational design of mRNA-based therapeutics and vaccines

ABSTRACT

Introduction

Messenger RNA (mRNA)-based therapeutics and vaccines have emerged as a disruptive new drug class for various applications, including regenerative medicine, cancer treatment, and prophylactic and therapeutic vaccinations.

Areas covered

This review provides an update about the rational structure-based design of various formats of mRNA-based therapeutics. The authors discuss the recent advances in the mRNA modifications that have been used to enhance stability, promote translation efficiency and regulate immunogenicity for specific applications.

Expert opinion

Extensive research efforts have been made to optimize mRNA constructs and preparation procedures to unleash the full potential of mRNA-based therapeutics and vaccines. Sequence optimization (untranslated region and codon usage), chemical engineering of nucleotides and modified 5ʹcap, and optimization of in vitro transcription and mRNA purification protocols have overcome the major obstacles (instability, delivery, immunogenicity and safety) hindering the clinical applications of mRNA therapeutics and vaccines. The optimized design parameters should not be applied as default to different biological systems, but rather individually optimized for each mRNA sequence and intended application. Further advancement in the mRNA design and delivery technologies for achieving cell type- and organ site-specificity will broaden the scope and usefulness of this new class of drugs.

KEYWORDS:

• In vitro transcribed (ivt) mRNA
• nucleoside-modified mRNA
• self-amplifying mRNA
• trans-amplifying mRNA
• mRNA vaccine
• regenerative medicine
• gene therapy

Article highlights

• The mRNA-based therapeutics are emerging as a novel strategy for gene therapy, regenerative medicine and vaccination.

• Recent advances in mRNA-based therapy provide notable advantages, including no risk of integration into the genomic DNA, adjustable gene expression and easier modulation of the immune system.

• The instability, immunogenicity, translation efficiency, and delivery of in vitro transcribed mRNA are the major hurdles limiting the development of mRNA-based therapeutics and vaccines.

• Various chemical modifications to in vitro transcribed mRNAs have been used to enhance mRNA stability, promote translation efficiency and achieve desirable immunogenicity for specific applications.

• Design of self-amplifying and trans-amplifying mRNAs represents promising approach to simplify administration and prolong therapeutic effect in patients.

Abbreviations

CDS = coding sequence; IVT mRNA – in vitro transcribed mRNA; LNP = lipid nanoparticle; MDA-5 = melanoma differentiation-associated protein 5; ORF = open reading frame; PEG = polyethylene glycol; PEI = polyethylene imine; RIG-I = retinoic acid inducible gene 1; RISC = RNA-induced silencing complex; RNP = ribonuclear protein; saRNA = self-amplifying RNA; taRNA = trans-amplifying RNA; TLR = toll-like receptor; UTR = untranslated region

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.