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š§¬š® They tied a giant gene
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Anthony Ao
August 14, 2025
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Intact introns enable fast, scarless circRNA: āCIRCā even circularizes fullālength dystrophin
Researchers report two ināvitro methods to make circular RNA (circRNA): PIET (Permuted IntronāExon through Transāsplicing) and CIRC (Complete selfāsplicing Intron for RNA Circularization). PIET exploits the second step of group I intron splicing using two RNA components; it allows timing control but did not outperform the widely used PIE approach in efficiency. By contrast, CIRC uses intact (unmodified) group I and group II introns, boosting circularization efficiency and speed under milder conditions while avoiding intron engineering. Using CIRC, the team circularized large constructsāincluding RNA encoding fullālength human dystrophin (~12,000 nt) and demonstrated expression of the 427ākDa proteināproduced āscarlessā circRNA with minimal immunogenicity, and showed that products can be purified with RNase R or via an oligo(dT)ābased workflow.
Why it matters
circRNA is attractive for therapeutics because itās stable and can drive protein production, but current circularization methods can be slow, require engineered introns, and complicate purification. CIRC lowers these barriersāworking with intact group I/II introns, under milder conditions, and at scales that reach very large genesābroadening the platformās utility for research and potential therapeutic applications.
ELI5 Summary
Imagine RNA as a ribbon of instructions. These scientists found simpler ways to tie that ribbon into a loop (called circular RNA) so it lasts longer and still makes proteins. They tried two tricks:
PIET: two RNA pieces snap togetherāgood for timing, but not more efficient than older methods.
CIRC: keeps RNAās own āselfāsplicingā parts intact, so the loop forms fast, under gentle conditions, and without extra āscarā bits.
CIRC even looped an extraālarge RNA that makes dystrophin (a huge muscle protein). The resulting loops were easier to clean up and showed low immuneātrigger signals in tests.
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Anthony Ao
The PhDLevel Team
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