Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy
Hammond SM., Hazell G., Shabanpoor F., Saleh AF., Bowerman M., Sleigh JN., Meijboom KE., Zhou H., Muntoni F., Talbot K., Gait MJ., Wood MJA.
Significance Splice-switching oligonucleotide (SSO) treatment in spinal muscular atrophy (SMA) has quickly become a clinical reality, but without an effective delivery system, the practicalities of delivering SSO therapy efficiently might preclude its widespread use. Our peptide-conjugated SSOs are being designed for clinical trials for the treatment of Duchenne muscular dystrophy. Here, we report advanced phosphorodiamidate oligomer (PMO) internalizing peptide (Pip) peptides that effectively deliver SSOs bodywide and at doses an order-of-magnitude lower than required by naked SSOs in a mouse model of SMA. Furthermore, our peptide-SSO is able to deliver to the CNS of adult mice. This study thus presents an oligonucleotide showing activity in the CNS following a systemic route with peptide delivery.