The small molecule Retro-1 enhances the pharmacological actions of antisense and splice switching oligonucleotides

Xin Ming (1) , Kyle Carver (1) , Michael Fisher (1) , Romain Noël (2) , Jean-Christophe Cintrat (2) , Daniel Gillet (3) , Julien Barbier (3) , Canhong Cao (1) , John Bauman (1) , Rudolph L. Juliano (1)

1 UNC - University of North Carolina [Chapel Hill]
2 SCBM - Service de Chimie Bio-Organique et de Marquage
3 SIMoS - Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO)

The attainment of strong pharmacological effects with oligonucleotides is hampered by inefficient access of these molecules to their sites of action in the cytosol or nucleus. Attempts to address this problem with lipid or polymeric delivery systems have been only partially successful. Here, we describe a novel alternative approach involving the use of a non-toxic small molecule to enhance the pharmacological effects of oligonucleotides. The compound Retro-1 was discovered in a screen for small molecules that reduce the actions of bacterial toxins and has been shown to block the retro-grade trafficking pathway. We demonstrate that Retro-1 can also substantially enhance the effectiveness of antisense and splice switching oligo-nucleotides in cell culture. This effect occurs at the level of intracellular trafficking or processing and is correlated with increased oligonucleotide accumulation in the nucleus but does not involve the perturbation of lysosomal compartments. We also show that Retro-1 can alter the effectiveness of splice switching oligonucleotides in the in vivo setting. These observations indicate that it is possible to enhance the pharmacological actions of oligonucleotides using non-toxic and non-lysosomotropic small molecule adjuncts.

Domaines: Chimie thérapeutique; Biotechnologies; Médicaments; Pharmacologie

Xin Ming, Kyle Carver, Michael Fisher, Romain Noël, Jean-Christophe Cintrat, et al.. The small molecule Retro-1 enhances the pharmacological actions of antisense and splice switching oligonucleotides. Nucleic Acids Research, 2013, 41 (6), pp.3673-3687. ⟨10.1093/nar/gkt066⟩. ⟨cea-02432369⟩