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PharmTech.com The Real Message Behind Commercial mRNA Products April eBook 2023 Pharmaceutical Technology ® 41 AnAly tics currently two approved mRNA therapeutics that are registered as SARS‑CoV‑2 vaccines (manufactured by Pfizer/BioNTech and Moderna) (1). These mRNA therapeutics carry the nucleic acid code to produce a protein (spike) antigen from the outer shell of the COVID‑19 virus (Figure 1) (2). Once this protein is synthesized, the individuals' immune system is stimulated to produce an immune response to the antigen, thereby helping with defence against future infection. In addition to their use as vaccines against viruses, other opportunities include the use of mRNA in immune‑oncology encoding patient‑specific cancer antigens and inducing immune responses against cancerous cells. mRNA therapeutics can also be utilized to pro‑ duce proteins that are endogenously lacking or ab‑ normal due to disease, an approach known as protein replacement therapy. This is a useful alternative to dosing w it h recombinant proteins, as m RNA‑de‑ rived proteins are synthesized within the patient's body. By producing proteins within the patient's body, all post‑translational modifications (PTMs) are host‑suitable and will not induce additional PTM‑de‑ rived toxicity, which can happen with recombinant proteins manufactured in non‑human cells (3). In situ production of therapeutic proteins, such as antibodies, can also reduce treatment costs, as the antibodies are produced with the patients' PTM machinery, which reduces the complexity of release testing of the phar‑ maceutical (4). In addition, this approach reduces the requirements for rigorous sterile cell culture protein manufacturing processes. Protein replacement ther‑ apy remains challenging because of the need for re‑ peated dosing, although there is a promising phase 1 clinical study investigating mRNA protein replace‑ ment therapy for cystic fibrosis (NCT03375047). The greatest opportunity for mRNA therapeutics is the ability to alter their nucleic acid sequence to code for any protein without significant changes to the overall chemistr y of the mRNA. This creates a pathway to the treatment of conditions that were otherwise undruggable in the past using small mol‑ ecules or antibodies. In addition, mRNA therapeutics produce the target protein without causing mutative effects because they do not alter the DNA sequence w it h i n t he nucleus (5). T he g reatest ch a l lenges c u r rent ly a s so c i ate d w it h m R NA t her ap e ut ic s are (i) immunotoxic effects from introducing foreign nucleic acids into the body and (ii) ensuring the mRNA gets to the target tissue within the body (targeted SARS-CoV-2 ssRNA (+) Envelope (E) Membrane (M) Nucleocapsid (N) Spike (S1 & S2) FIGURE 1. Schematic structure of SARS-CoV-2 virus. The structural spike protein attaches to the human host cells during infection. mRNA vaccines for SARS-CoV-2 enable the body to produce this antigen to induce immune responses. Adapted and reproduced with permission from reference 2 under a Creative Commons Attribution 4.0 International License: https://creativecommons.org/licenses/by/4.0/. FIGURES COURTESY OF THE AUTHOR.