Current and future therapies for inherited cholestatic liver diseases

Figure 3 Schematic of the binding of U1 snRNA to exon-intron boundaries to initiate the splicing process. Disease-associated nucleotide changes can affect the recruitment of the cellular splicing machinery, resulting in splice defects. Modification of the U1 snRNA sequence to restore base-pairing between U1 snRNA and the exon-intron boundary can restore splicing. The use of exon-specific U1 constructs, binding at less conserved intronic regions (ExSpe U1 snRNA), may reduce the risk of off-target effects. Simultaneously, ExSpe U1 snRNAs are likely to be effective in a higher number of patients as they can restore splice defects due to several distinct mutations within a certain exon-intron boundary.