This presentation detailed the development of novel LNA-based oligonucleotides for RNA targeting, focusing on single-stranded approaches, challenges, and new modifications. Jesper Wengel, Professor at the Nucleic Acid Centre in University of Southern Denmark, provided an overview of the field, particularly his team’s work with single-stranded antisense oligonucleotides and blockmir approaches.
Challenges in antisense oligonucleotides include achieving a therapeutic window, delivery issues, and the debate over phosphorothioate mixtures versus stereopure compounds. Wengel noted how phosphorothioate antisense oligonucleotides have strong protein-binding capabilities, offering pharmacokinetic advantages but also posing off-target effects.
Their lab has developed various RNA modifications, including locked and unlocked analogues, enabling fine-tuning of properties and specificity. Fatty acid-conjugated antisense oligonucleotides, specifically palmitoylated amino LNAs, showed potential for improved pharmacokinetics and biodistribution. These constructs demonstrated strong albumin binding and different biodistribution patterns in mice.
Gene silencing potency was observed with Di-Pal constructs, particularly with gymnotic delivery. Collaborative work with Professor Edvard Smith at Karolinska Institutet on targeting the Huntington gene with antisense LNA oligonucleotides showed promising results, especially with palmitoylated variants.
The presentation also discussed conjugates between cell-penetrating peptides and antisense oligonucleotides, highlighting their potential in overcoming aggregation challenges. Wengel also introduced their blockmir approach for gene upregulation, showing potential in proof-of-concept studies without toxicity.
In conclusion, the presentation provided insights into the advancements and challenges in the field of LNA-based oligonucleotides for RNA targeting, emphasising the importance of balancing therapeutic efficacy and off-target effects. Wengel concluded by acknowledging the contributions of collaborators and expressed optimism for future developments.