mRNA transcript therapy

Abstract

mRNA is the central molecule of all forms of life. It is generally accepted that current life on Earth descended from an RNA world. mRNA, after its first therapeutic description in 1992, has recently come into increased focus as a method to deliver genetic information. The recent solution to the two main difficulties in using mRNA as a therapeutic, immune stimulation and potency, has provided the basis for a wide range of applications. While mRNA-based cancer immunotherapies have been in clinical trials for a few years, novel approaches; including, in vivo delivery of mRNA to replace or supplement proteins, mRNA-based generation of pluripotent stem cells, or genome engineering using mRNA-encoded meganucleases are beginning to be realized. This review presents the current state of mRNA drug technologies and potential applications, as well as discussing the challenges and prospects in mRNA development and drug discovery.

Keywords:

• modified nucleoside
• mRNA
• PKR
• pseudouridine
• purification
• therapeutic protein
• vaccine

Financial & competing interests disclosure

D Weissman is named in patents describing nucleoside modified mRNA as a therapeutic. The author has no other 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 apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• mRNA delivers therapeutic proteins to cells in vitro and in vivo, but its intrinsic immunogenicity has limited clinical development to mainly vaccine studies.

• Nucleoside modification reduces the ability of in vitro transcribed RNA to activate RNA innate immune sensors.

• The further removal of phage polymerase produced contaminants, namely double-stranded RNA, can completely ablate the immunogenicity of RNA containing certain nucleoside modifications.

• mRNA encoding a variety of antigens is an effective vaccine approach that can be delivered by direct injection of mRNA or ex vivo treatment of cells.

• A major hurdle to mRNA therapeutics is the development of safe and effective in vivo delivery technologies, which is further complicated when the targeting of particular cells or organs is required.

• mRNA therapy has therapeutic advantages, no risk of chromosomal integration, high transfection efficiency in both dividing and non-dividing cells, superior modulation of the amount and duration of protein production, in many different fields, including vaccines, protein replacement, genome editing, cell fate reprogramming and cancer immunotherapy.

• Nucleoside-modified mRNA has the potential to revolutionize protein therapeutics, but is at an early stage of development and requires optimization and understanding of all elements of production and use.

Notes