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.