Lipophilic Conjugation Enhances ASO Efficacy for Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder caused by mutations in the DMD gene, leading to progressive muscle degeneration. Antisense oligonucleotides (ASOs) have emerged as a promising therapeutic strategy through exon skipping to restore functional dystrophin production.

Study Objective

This study investigates the conjugation of ASO targeting exon 51 (ASO 51) with lipophilic compounds, particularly ursodeoxycholic acid (UDCA) and other bile acids, to enhance exon skipping efficiency. Researchers synthesized several ASO-lipid conjugates and evaluated their exon-skipping potency in myogenic cells.

Key Findings

• 5′-UDC-ASO 51 and 5′,3′-bis-UDC-ASO 51 showed significantly higher exon skipping efficiency compared to unconjugated ASO 51.
• The lipophilic modifications facilitated improved uptake and formation of nanoparticle-like aggregates in aqueous media.
• Gymnotic (passive) uptake of lipophilic ASOs demonstrated enhanced cellular delivery.
• 5′-UDC-ASO 51 exhibited optimal exon skipping with full phosphorothioate (PS) linkages, while reducing PS content lowered efficiency.

Conclusion

These results suggest that lipophilic conjugation of ASOs can significantly improve their therapeutic efficacy in DMD by enhancing uptake, stability, and exon skipping potency.