Antisense oligonucleotide (ASO) have been under clinical investigation over the last 30 years. The development and optimization of their chemistry has led to a recent increased number of FDA approvals and clearly confirmed the value of this alternative therapeutical approach. However, their broad application is still hampered by their limited productive uptake by cells outside the liver. While numerous targeted delivery approaches have been studied to circumvent this issue, the selective application of ASOs to extra hepatic targets remains a formidable challenge.<br/>We will report on a novel strategy based on ASO conjugation to a glucagon like peptide receptor (GLP1R) agonist. This approach has enabled the successful productive internalization of ASO conjugate in pancreatic beta cells - a cell type so far refractory to ASO uptake - and translated into remarkable selectivity for gene silencing in the targeted cell population compared to liver.<sup>1</sup><br/>The presentation will encompass the design of these conjugates with emphasis on the impact of the chemistries of the different components: ASO, targeting peptide and linker. We will outline the challenges associated with the synthesis and profiling of these novel conjugates as well as the future perspective for this novel ASO delivery method.

Design, synthesis, and application of GLP1 agonist-ASO conjugates to gene silencing in pancreatic beta cells

2019 Spring National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.