Variables and Strategies in Development of Therapeutic Post-Transcriptional Gene Silencing Agents

Figure 6

mRNA repair strategy for Dominant Mutations. The trans-splicing group I intron of Tetrahymena is engineered with an element that contains a WT mRNA sequence starting from just upstream of the mutation(s) in the target mRNA (labeled X). The Group I intron recognizes the region upstream of the target by way of complementary base pairing. It then cleaves the target using free guanosine as a nucleophile and then trans-splices a fresh downstream WT target mRNA element at the precise site of cleavage. All mutations in a given gene below the splice site could be treated with a single trans-splicing group I intron. One or several engineered group I introns could cover most mutations in a given human gene.