Systematic Approach to Developing Splice Modulating Antisense Oligonucleotides

Splice-switching antisense oligonucleotides as therapeutic drugs

Splice-switching oligonucleotides (SSOs) are short, synthetic, antisense, modified nucleic acids that base-pair with a pre-mRNA and disrupt the normal splicing repertoire of the transcript by blocking the RNA-RNA base-pairing or protein-RNA binding interactions that occur between components of the splicing machinery and the pre-mRNA. Splicing of pre-mRNA is required for the proper expression of...

A Sensitive Assay System To Test Antisense Oligonucleotides for Splice Suppression Therapy in the Mouse Liver

We have previously demonstrated the efficacy of antisense therapy for splicing defects in cellular models of metabolic diseases, suppressing the use of cryptic splice sites or pseudoexon insertions. To date, no animal models with these defects are available. Here, we propose exon skipping of the phenylalanine hydroxylase (Pah) gene expressed in liver and kidney to generate systemic hyperphenyla...

Designing Antisense Oligonucleotides

Antisense Oligonucleotides Targeting Protein

Designing Antisense Oligonucleotides

Antisense oligonucleotides have been used for a number of years to modify the expression of specific genes both in vivo and in vitro (Scanlon et al., 1995). The most potent mode of antisense activity is through RNase H–mediated degradation of RNA (Figure 1). The RNase H– endonuclease specifically cleaves RNA only when it is hybridized as a heteroduplex with DNA. In general, oligonucleotides tha...