Neutral Surfactant Enhanced Exon-skipping of Morpholino Oligonucleotides in vitro and in mdx Mice

Abstract

Antisense oligomers induced exon-skipping has been promising therapy for Duchenne muscular dystrophy in preclinical and clinical trials, but its therapeutic potential could be improved with enhanced delivery approach. A few neutral surfactants were investigated here in for their performance to improve exon-skipping of an antisense phosphorodiamidate morpholino oligomer (PMO) both in vitro and in vivo. This study showed that these surfactants, especially Bigchapand Deoxy Bigchap, improved the delivery efficiency of PMO to the levels comparable to Endoporter-mediated PMO delivery in vitro, and significant enhancement with Deoxy Bigchap-mediated PMO was further observed in mdx mice up to 7-fold compared with PMO alone. Cytotoxicity of the surfactants except for Mega10 was much lower than that by Endoporter in vitro and not clearly observed in vivo under the tested dosage. These results reveal that surfactant’s composition is key factor as delivery carrier to improve PMO exon-skipping efficiency, the efficacy and safety endow neutral surfactants as potential delivering enhancer for oligonucleotide in the treatment of muscular dystrophy or other diseases.