Our results demonstrated that 2′-modified RNA PS ASOs containing four or less PS DNA nucleotides at the 3′-end yielded improved exon 23 skipping efficacy in line with fully modified ASO controls. For this purpose, a four-nucleotide DNA segment was systematically incorporated into a 20-mer 2′-OMe PS and 2′-MOE PS ASO designed to skip exon 23 in mdx mouse myotubes in vitro.
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Towards this goal, in this study, we evaluated the potential of incorporating DNA segments at appropriate sites in 2′-OMe PS and 2′-MOE PS ASOs to induce exon skipping. The potency of 2′-modified RNA for splice-switching needs to be further improved by novel design strategies for broad applicability. Although systemic delivery of PMOs has displayed a good safety profile even at high doses, the 2′- O-methyl phosphorothioate modified (2′-OMe PS) ASO drug candidate (drisapersen) failed due to safety issues. Notably, three among them (Exondys 51, Vyondys 53 and Viltepso) are based on phosphorodiamidate morpholino (PMO) chemistry whereas Spinraza is based on 2′- O-methoxyethyl phosphorothioate (2′-MOE PS) chemistry.
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So far, nine ASO drugs have received approval for clinical use, and four of them are based on splice-switching principles demonstrating the impact of ASO-mediated splice modulation. Synthetic antisense oligonucleotides (ASOs) have emerged as one of the most promising therapeutic approaches.