V. Narry Kim's team triples mRNA lifespan using viral RNA survival strategies

Researchers have found a new way to extend the lifespan of next-generation mRNA vaccines and treatments by more than threefold, drawing on RNA survival strategies that viruses have refined over millions of years of evolution.

The Ministry of Science and ICT announced that a research team led by V. Narry Kim, director of the Institute for Basic Science's RNA Research Center and a distinguished professor at Seoul National University, conducted a large-scale genomic analysis of 337 virus species that infect vertebrates, identifying regulatory elements that enhance RNA stability and protein production and uncovering the mechanisms behind them.

The findings were published Friday in the international journal Cell (Korean Standard Time).

Viruses must make their genetic information work efficiently inside host cells using only a very small genome. To do so, they have evolved to make precise use of the host cell's RNA regulatory systems.

When the poly(A) tail at the end of an mRNA shortens, the RNA becomes vulnerable to degradation. Viruses have evolved a range of RNA protection strategies to prevent this.

The research team divided the genomes of 337 virus species spanning 297 viral genera into roughly 200,000 RNA fragments, synthesized them and analyzed them in massively parallel fashion. The team identified 23 regulatory elements that enhance RNA stability and protein production by exploiting TENT4, a previously known RNA regulatory enzyme. The elements were distributed across 19 viral genera and classified into at least six types based on their sequence and structure.

The team paid particular attention to one element, "Pt1," among newly discovered regulatory elements that do not rely on TENT4. Pt1, found in the 3′ UTR of the eel picornavirus (Potamipivirus), directly recruits PAP, the enzyme that synthesizes the poly(A) tail — a mechanism distinct from existing approaches.

Pt1 slows mRNA degradation by using PAP to continuously replenish the shortening poly(A) tail. The team named viral RNA regulatory elements that exploit the host's RNA tail-regulating enzymes in this way "tailons."

When Pt1 was applied to linear mRNA, the poly(A) tail grew from 60 to as many as 194 nucleotides. As a result, the mRNA's intracellular half-life increased nearly threefold, from 7.6 hours to 23.1 hours. The team said the stability of linear mRNA had been raised to a level approaching that of circular RNA.

The research is significant in that it offers a new method for extending RNA lifespan while preserving the linear mRNA format, which is comparatively easier to manufacture. The technology holds potential as a way to improve the durability of mRNA vaccines and treatments.

"This is an achievement that reveals, on a large scale, the sophisticated strategies viruses use to exploit the host cell's RNA regulatory systems," V. Narry Kim said. "The regulatory elements we have identified will serve as molecular tools to overcome the limitations of existing mRNA treatment technologies and substantially improve the durability of therapeutic effects."