Single alkyl phosphonate modification of the siRNA backbone in the seed region enhances specificity and therapeutic profile.

ABSTRACT: We evaluated the effect of alkyl phosphonate linkages in enhancing the specificity and therapeutic profile of siRNA when incorporated into the seed region. siRNAs modified with a single alkyl phosphonate linkage demonstrated enhanced specificity and therapeutic profile compared to the parent siRNA. We found that these modifications are most effective when positioned at the internucleotide linkages 6-7 from the 5'-end of the guide strand. Our findings reveal that siRNAs with this modification maintain robust on-target activity both in vitro and in vivo. Importantly, differential gene expression (DGE) analysis showed a significant reduction in off-target effects across in vitro and in vivo, leading to an improved therapeutic profile. We also demonstrate enhanced safety in mice, as evidenced

SUBMITTER: Nikan M 

PROVIDER: S-EPMC12309379 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature