Systemic delivery of a splice-switching oligonucleotide heteroduplex corrects splicing in central nervous system and muscle in spinal muscular atrophy mice

Abstract

ABSTRACTOligonucleotide therapeutics are an established class of drugs for the treatment of genetic disorders. Their clinical development is challenging, however, as they typically distribute poorly to extra-hepatic tissues after systemic injection. Here we tested the heteroduplex oligonucleotide (HDO) platform for systemic delivery ofSMN2splice-switching oligonucleotides of 2’-O-methoxyethyl phosphorothioate or phosphorodiamidate morpholino oligomer chemistries. We first showed that splice-switching HDO cargoes correctSMN2splicing in cells derived from spinal muscular atrophy (SMA) patients, and validated extra-hepatic activity in spinal cord and muscle in a mouse model of SMA following systemic delivery. Our study raises prospects for delivery of nusinersen, the 2’-O-methoxylethyl phosphorothioate oligonucleotide therapy approved for SMA and currently delivered by intrathecal injection, by systemic injection exploiting the HDO chemistry platform. Our findings also suggest that oligonucleotide drugs lacking convincingin vivoefficacy in muscle tissue could be delivered effectively by the HDO technology.