Categories: Past WebinarsPublished On: January 12th, 2024



Time: 8AM PST | 11AM EST | 5PM CET
Date: February 29, 2024

Title: Towards Allele-Selective Gapmer ASO Design

Description: Allele selective gapmer antisense oligonucleotides (ASOs) are a promising strategy for the treatment of rare monogenic neurodevelopmental disorders caused by gain-of-function or dominant negative variants. These selective gapmers are able to discriminate between two mRNAs that differ by only a single nucleotide, such as point mutations or single nucleotide polymorphisms. To get a better understanding of how best to achieve this selectivity, we investigated the effect of specific mismatches in the DNA gap on a gapmer’s discriminatory potential. We found that our gapmers can discriminate between a single nucleotide difference with a selectivity ranging from 2.6 (dC-rG over dC-rU) to 552 (dG-rC over dG-rU) for the targeted over the mismatched sequence. Although a larger dataset with more diverse gapmer and target sequences is required to generalize our findings, this work could help in providing a framework for allele-selective gapmer design.


Emilio Harris-Mostert
Department of Clinical Genetics, Erasmus MC in Rotterdam

Title: Synthesis, Characterization, and Biological Evaluation of Novel 3- Component Lipid Nanoparticles for mRNA Delivery

Description: Lipid nanoparticles (LNPs) are an effective and broad class of delivery vehicles for genetic cargo that have found clinical application for delivery of siRNAs to treat genetic liver diseases and mRNA vaccines. We report the synthesis of novel zwitterionic amino lipids (ZALs), a class of delivery materials that has shown efficacy for mRNA delivery. ZALs were designed to combine the chemistry of the ionizable amino lipid and the zwitterionic phospholipid into a single molecule to allow formulation of 3-component LNPs with enhanced molecular interactions between the amphipathic lipids and mRNA molecules in water pockets within the LNP. A key attribute of the zwitterionic amino lipid is the introduction of secondary hydroxyl groups following ring-opening of alkyl epoxides that could participate in hydrogen bonding. We systematically investigated the secondary hydroxyl position within ZA3-Ep10, a lead ZAL that emerged from the initial high-throughput screen as being able to effectively deliver mRNA in vitro and in vivo.


Joshua Robinson
Graduate Student
UT Southwestern Medical Center