Effect of modular conjugation strategy for N-acetylgalactosamine-targeted antisense oligonucleotides

Abstract

The asialoglycoprotein receptor (ASGPr) and N-acetylgalactosamine (GalNAc) is one of the most reliable receptor-ligand combinations for delivering antisense oligonucleotides (ASOs) to the liver. Here, we show that a modular GalNAc conjugation strategy allows us to reinforce the activity of the parent, naked 2′,4′-BNA/LNA gapmer targeting apolipoprotein B. The conjugation partly reduced a possible hepatotoxicity of the parent ASO. The structure-activity study revealed the significance of the metabolic susceptibility of the GalNAc moiety to nucleolytic cleavage that results in exposure of the parent gapmer. The broad usefulness of our delivery strategy of ASOs to the liver has been demonstrated.

Keywords:

• Antisense oligonucleotides
• 2′,4′-BNA/LNA
• ligand-targeted drug delivery
• asialoglycoprotein receptor
• N-acetylgalactosamine

Additional information

Funding

Japan Agency for Medical Research and Development; Japan Society for the Promotion of Science; Japanese Ministry of Health, Labor, and Welfare.