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🧬😼 They tied a giant gene

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Anthony Ao
August 14, 2025

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Intact introns enable fast, scarless circRNA: “CIRC” even circularizes full‑length dystrophin

Researchers report two in‑vitro methods to make circular RNA (circRNA): PIET (Permuted Intron‑Exon through Trans‑splicing) and CIRC (Complete self‑splicing 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 constructs—including RNA encoding full‑length human dystrophin (~12,000 nt) and demonstrated expression of the 427‑kDa protein—produced “scarless” circRNA with minimal immunogenicity, and showed that products can be purified with RNase R or via an oligo(dT)‑based workflow.

Why it matters

circRNA is attractive for therapeutics because it’s stable and can drive protein production, but current circularization methods can be slow, require engineered introns, and complicate purification. CIRC lowers these barriers—working with intact group I/II introns, under milder conditions, and at scales that reach very large genes—broadening the platform’s 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 together—good for timing, but not more efficient than older methods.

  • CIRC: keeps RNA’s own “self‑splicing” parts intact, so the loop forms fast, under gentle conditions, and without extra “scar” bits.

CIRC even looped an extra‑large RNA that makes dystrophin (a huge muscle protein). The resulting loops were easier to clean up and showed low immune‑trigger signals in tests.

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Stay curious,
Anthony Ao
The PhDLevel Team
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