Conceptual and translational pitfalls of mmRNA drug development
The paper critically examines the design of base-modified messenger RNA (mmRNA) used in COVID-19 vaccines (and potentially other therapeutics). It was prompted by updated safety warnings involving increased risks of myocarditis/pericarditis, among other health problems. The paper argues that the approach rests on flawed assumptions and creates significant risks.
Core problems identified:
A)
Excessive and non-natural modifications: Vaccine mRNA replaces roughly 50% of uridine bases with N1-methyl-pseudouridine. Natural eukaryotic (human) mRNA contains only about 0.2–0.6% pseudouridine (Ψ/U ratio), and methylation of this type is absent in coding regions. The claim that these modifications are “natural and common” is misleading.
B)
Ignoring natural mRNA turnover: The modifications are intended to stabilize the mRNA and reduce immune recognition. This bypasses the body’s normal rapid breakdown of mRNA, which acts as a safety feature. The result can be prolonged production of spike protein with an unknown duration (pharmacological half-life).
C)
Translation errors and off-target products: The modifications can promote ribosomal frameshifting (reading the genetic code out of frame), producing abnormal proteins. There is also concern about reverse transcription via polymerase theta and uncontrolled spike protein production.
D)
Interference with innate immunity: The structural changes may impair RNase L, a key enzyme that degrades viral RNA and limits viral protein synthesis.
E)
Conceptual confusions: Researchers have often mixed up the biology of transfer RNA (tRNA, which is heavily modified) with coding mRNA, and conflated different base modifications (e.g., pseudouridine vs. N6-methyladenosine).
Overall conclusion: Because of these conceptual, procedural, and translational pitfalls and substantial unknowns, a careful re-evaluation is needed before broadly using mmRNA therapeutics in healthy people of all ages, including pregnant women.
Please read the article at the link: https://doi.org/10.1186/s40246-026-01061-3
Conceptual and translational pitfalls of modified messenger RNA drug design with public health impact. Human Genomics (2026).
Boros, L.G., Brogna, C., Browner, C.H., Piscopo, M., Kyriakopoulos, A.M., Seneff, M.
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