Breakthroughs in mRNA design have enabled the rapid development of new therapeutics, with CleanCap® technology playing a central role in the success of the Pfizer/BioNTech COVID-19 vaccine. While optimized caps and modified nucleotides have proven essential, expanding mRNA medicines into broader therapeutic areas will require continued innovation.
CleanCap® M6, TriLink’s most advanced cap analog, delivers significantly higher in vivo protein expression than previous industry standards. This improvement is driven in part by reduced decapping by Dcp2, enabling greater potency at equivalent doses.
Attention is also turning to the 3′ end of the mRNA molecule, where strategic modifications to the poly(A) tail can improve stability and extend protein expression by resisting exonuclease degradation. To advance this approach, TriLink evaluated multiple candidates and identified a lead solution.
This technical note introduces ModTail™, a novel poly(A) tail modification that enhances both total protein expression and duration of expression across multiple N1MePsU-mRNA constructs. These benefits were demonstrated in vitro and in vivo, positioning ModTail as a powerful complement to next-generation cap technologies like CleanCap M6.
We present the following in this tech note:
- ModTail chemistry is added to mRNA with high efficiency and with no measurable impact on mRNA capping efficiency, purity, or dsRNA levels
- Compatibility of ModTail chemistry with various cap structures, tail lengths, and types of mRNA constructs
- ModTail mRNA increases in vitro and in vivo protein expression and duration of expression
- The possibility that higher protein expression with ModTail possibly lowers the dosage of mRNA needed to provide the same therapeutic effect