Novel endosomolytic compounds enable highly potent delivery of antisense oligonucleotides

• DOI: 10.1038/s42003-022-03132-2
• Publication Date: 2022-03-01T11:03:01Z
• Authors: Jeremy P. Bost; Miina Ojansivu; Michael J. Munson; Emelie Wesén; Audrey Gallud; Dhanu Gupta; Oskar Gustafsson; Osama Saher; Julia Rädler; Stuart G. Higgins; Taavi Lehto; Margaret N. Holme; Anders Dahlén; Ola Engkvist; Per-Erik Strömstedt; Shalini Andersson; C. I. Edvard Smith; Molly M. Stevens; Elin K. Esbjörner; Anna Collén; Samir El Andaloussi
• Keywords: Creatures; LAMP1

Abstract The therapeutic and research potentials of oligonucleotides (ONs) have been hampered in part by their inability to effectively escape endosomal compartments reach cytosolic nuclear targets. Splice-switching ONs (SSOs) can be used with endosomolytic small molecule compounds increase functional delivery. So far, development these has hindered a lack high-resolution methods that correlate SSO trafficking activity. Here we present in-depth characterization two novel using combination microscopic assays high spatiotemporal resolution. This system allows the visualization trafficking, evaluation membrane rupture, quantitates activity on protein level presence compounds. We confirm leakage into cytosol occurs parallel physical engorgement LAMP1-positive late endosomes lysosomes. conclude new interfere while inducing rupture concurrent ON cytosol. efficacy advocates use as novel, potent, quick-acting transfection reagents for antisense ONs.