Splice-switching antisense oligonucleotides (SSOs) are emerging as treatments for neuromuscular diseases, with several SSOs currently undergoing clinical trials. Recently eteplirsen (EXONDYS 51), an SSO based on morpholino chemistry targeting exon-51 skipping of dystrophy has been approved by FDA for treatment of Duchenne muscular dystrophy (DMD). However, therapeutic development of SSO has been hampered by poor cellular uptake and tissue penetration, including crossing of the blood-brain barrier (BBB) to reach targets in the central nervous system (CNS). For spinal muscular atrophy (SMA) application, we have investigated the ability of BBB-crossing peptides for CNS delivery of splice-switching phosphorodiamidate morpholino oligonucleotides (PMO) targeting survival motor neuron-2 (SMN2) exon 7 inclusion. We identified a branched derivative of the well-known ApoE (141-150) peptide, which as a PMO conjugate was capable of exon inclusion in the CNS following systemic administration, leading to the restoration of a full-length SMN2 transcript. Treatment of newborn SMA mice with this peptide-PMO conjugate resulted in a significant increase in the average lifespan, increase in weight, muscle strength and righting reflexes. Treatment of adult SMA mice with this newly identified peptide-PMO also resulted in a significant increase in the level of SMN expression in the CNS. This work provides proof of principle for the ability to select new peptide paradigms to enhance CNS activity of a PMO. We hope further peptide sequence refinement will enable this new peptide-based delivery platform to be developed for CNS delivery of PMO SSOs for the treatment of neuromuscular and neurodegenerative diseases.