RNA to the rescue: RNA is one of the most promising targets for drug development given its wide variety of uses

Abstract

The race for a vaccine against SARS-CoV-2 has accelerated research on RNA-based therapeutics. Beyond vaccines, RNA also shows great potential for cancer therapies.

Figure 1. RNA interference and its discovery

The Nobel Prize in Physiology or Medicine for 2006 was awarded jointly to Andrew Fire and Craig Mello “for their discovery of RNA interference—gene silencing by double‐stranded RNA”, a fundamental mechanism of gene regulation. © Annika Röhl/The Nobel Committee for Physiology or Medicine.

Figure 2. Coronavirus @ Molecular Landscapes

This painting depicts a coronavirus just entering the lungs, surrounded by mucus secreted by respiratory cells, secreted antibodies, and several small immune systems proteins. The painting is based on information about the SARS virus. Illustration by David S. Goodsell, RCSB Protein Data Bank, PDB‐101 (PDB101.rcsb.org); https://doi.org/10.2210/rcsb_pdb/goodsell-gallery-019. Reproduced with permission.

Figure 3. Conceptual framework for the production of mRNA vaccines

Two categories of mRNA constructs are being actively evaluated. Non‐replicating mRNA (NRM) constructs encode the coding sequence (CDS) and are flanked by 5′ and 3′ untranslated regions (UTRs), a 5′‐cap structure and a 3′‐poly‐(A) tail. The self‐amplifying mRNA (SAM) construct encodes additional replicase components able to direct intracellular mRNA amplification. (1) NRM and SAM are formulated in this illustration in lipid nanoparticles (LNPs) that encapsulate the mRNA constructs to protect them from degradation and promote cellular uptake. (2) Cellular uptake of the mRNA with its delivery system typically exploits membrane‐derived endocytic pathways. (3) Endosomal escape allows release of the mRNA into the cytosol. (4) Cytosol‐located NRM constructs are immediately translated by ribosomes to produce the protein of interest, which undergoes subsequent post‐translational modification. (5) SAM constructs can also be immediately translated by ribosomes to produce the replicase machinery necessary for self‐amplification of the mRNA. (6) Self‐amplified mRNA constructs are translated by ribosomes to produce the protein of interest, which undergoes subsequent post‐translational modification. (7) The expressed proteins of interest are generated as secreted, trans‐membrane, or intracellular protein. (8) The innate and adaptive immune responses detect the protein of interest. Reproduced from (Jackson et al, 2020), with permission.

Figure 4. Personalized mRNA‐based antitumor vaccines

The exome of tumor cells isolated from a biopsy sample and the exome of normal cells are compared to identify tumor‐specific mutations. Point non‐synonymous mutations, gene deletions, or rearrangements can give rise to neoantigens. Several bioinformatics tools are used to predict major histocompatibility complex (MHC) class I and class II binding (necessary for recognition by T cells) and RNA expression presence of the mutated antigen among tumor cells (clonality). RNA sequencing enables verification that the gene encoding the neoantigen is actually expressed by tumor cells. A tandem gene encoding several neoantigen peptides is cloned into a plasmid and transcribed to mRNA. Finally, these mRNAs are injected as naked RNA, formulated into liposomes or loaded into dendritic cells. Reproduced from (Pastor et al, 2018), with permission.