RNA Therapeutics: A Healthcare Paradigm Shift

Abstract

COVID-19 brought about the mRNA vaccine and a paradigm shift to a new mode of treating and preventing diseases. Synthetic RNA products are a low-cost solution based on a novel method of using nucleosides to act as an innate medicine factory with unlimited therapeutic possibilities. In addition to the common perception of vaccines preventing infections, the newer applications of RNA therapies include preventing autoimmune disorders, such as diabetes, Parkinson's disease, Alzheimer's disease, and Down syndrome; now, we can deliver monoclonal antibodies, hormones, cytokines, and other complex proteins, reducing the manufacturing hurdles associated with these products. Newer PCR technology removes the need for the bacterial expression of DNA, making mRNA a truly synthetic product. AI-driven product design expands the applications of mRNA technology to repurpose therapeutic proteins and test their safety and efficacy quickly. As the industry focuses on mRNA, many novel opportunities will arise, as hundreds of products under development will bring new perspectives based on this significant paradigm shift-finding newer solutions to existing challenges in healthcare.

Keywords: PCR; affordable therapies; autoimmune disorders; mRNA; repurposing drugs; ribonucleic acid (RNA); therapeutic proteins; vaccines.

Figure 1

Mechanisms of RNA therapeutics [5] (Via license: CC BY-NC-ND 4.0). anti-miRNA (A); miRNA mimics (B); block-miRNA agonists (C); RNA-induced silencing complex (RISC) (D,E1,E2); splicing process of mRNA (F); intracellular enzyme RNase H (G). Key: shRNA—short hairpin RNA; pri-miRNA—primary miRNA; pre-miRNA—precursor miRNA; TRBP—Tar RNA binding protein; AGOs—argonautes; Pol II—RNA polymerase II; siRISC—siRNA-induced silencing complex; miRISC—miRNA-induced silencing complex.

Figure 2

Chemical structures of mRNA modifications. Chemical structures in eukaryotic mRNA, including m⁶A, m¹A, m⁵C, hm⁵C, Ψ, I, U, and 2′-O-Me. m⁶A is mostly found in the 3′UTRs as well as the 5′UTRs; m¹A-containing mRNA is 10 times less common than m⁶A-containing mRNA, but it is found in all segments of mRNA; m⁵C is found in both coding and non-coding regions, especially in GC-rich regions, where it regulates transcription differently; Ψ appears in many locations; 2′-O-Me is concentrated in the mRNA region that encodes amino acids.

Figure 3

Typical DNA, pre-MRNA, and mRNA design sequences; UTR—untranslated region; poly(A)—polyadenylate signal tail (enumver as beeded [36]). The 5′ cap at the end allows for sequence recognition, protecting the translated molecules from digestion by nucleases [37]. The 5′UTR/3′UTR determines the translation efficiency, stability, and location; it is pivotal to optimizing expression [36,38]. The open reading frame or coding sequence (CDS) lists the genes expressed. These genes are optimized and modified to improve translational efficiencies, such as the modification of guanine and cytosine content [39]. The Poly(A) tail is essential for optimal translation 11 and improves stability by blocking digestion by 3′ exonuclease, increasing translation efficiency and adding to the molecule’s stability [40].

Figure 4

Plasmid DNA is designed to produce mRNA for a COVID-19 vaccine.