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Group I intron ribozymes can repair mutated mRNAs by replacing the 3′-terminal portion of the mRNA with their own 3′-exon. This  trans -splicing reaction has the potential to treat genetic disorders and to selectively kill cancer cells or virus-infected cells. However, these ribozymes have not yet been used in therapy, partially due to a low in vivo  trans -splicing efficiency. Previous strategies to improve the  trans -splicing efficiencies focused on designing and testing individual ribozyme constructs. Here we describe a method that selects the most efficient ribozymes from millions of ribozyme variants. This method uses an in vivo rescue assay where the mRNA of an inactivated antibiotic resistance gene is repaired by  trans -splicing group I intron ribozymes. Bacterial cells that express efficient  trans -splicing ribozymes are able to grow on medium containing the antibiotic chloramphenicol. We randomized a 5′-terminal sequence of the  Tetrahymena thermophila  group I intron and screened a library with 9 × 10 6  ribozyme variants for the best  trans -splicing activity. The resulting ribozymes showed increased  trans -splicing efficiency and help the design of efficient  trans -splicing ribozymes for different sequence contexts. This in vivo selection method can now be used to optimize any sequence in  trans -splicing ribozymes.

An in vivo selection method to optimize trans-splicing ribozymes