Title : Systemic liver-targeting delivery of a novel DNA/RNA heteroduplex oligonucleotide via an enteral route
Since the advent of antisense technology, oligonucleotide drugs have attracted a greater deal of attention as next-generation therapeutics, which can be selectively delivered to their target tissue to obtain effective gene silencing. The production of conventional pharmaceutical preparations considering factors such as the oral and rectal dosage form is an essential step in the development of a wide range of oligonucleotide drugs. However, oligonucleotides are macromolecules that are easily disintegrated by nucleases and as such, are generally poorly absorbed by the intestine. We have recently developed a hepatocyte-specific delivery technique for oligonucleotides via an enteral route. The chemical conjugation of siRNA with alpha-tocopherol utilized chylomicrons, which acted as a specific in vivo carrier to the liver and were formulated as lipid nanoparticles using unsaturated fatty acid as an absorption enhancer. The method demonstrated effective silencing of the targeted mRNA (ApoB) expression in mice in a postprandial state (Murakami, et al, Sci. Rep. 2015). In this talk, we will provide an overview of the concept of our enteral delivery technique and discuss our recent results on the development of a DNA/RNA heteroduplex oligonucleotide (HDO) which was newly prepared as a more specific and potent oligonucleotide drug (Nishina K., et al. Nat. Commun., 2015). We used a tight junction (TJ) modulator as a para-cellular specific permeation enhancer (Takahashi A, et al., Biomaterials, 2012) and demonstrated that the HDO conjugate with alpha-tocopherol specifically delivered to the liver following rectal administration of the enema in mice and suppressed ApoB gene expression, consequently achieved the reduction of plasma triglyceride and cholesterol levels in the model mice with hypercholesterolemia. These findings suggest that our enteral delivery technique via the lymphatic route should be useful for developing a non-invasive conventional preparation for oligonucleotide therapeutics. Applicability of this technology to the other organ-specific oligonucleotide delivery systems using conjugates with different targeting molecules or ligands remains to be investigated.
Audience take away:
• Recent development of novel oligonucleotide technology and therapeutics.
• Conceptualization and development of an enteral delivery system for oligonucleotide therapeutics.
• Technology and the benefits of systemic delivery via the enteral lymphatic route.