Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy

Proc Natl Acad Sci U S A. 2016 Sep 27;113(39):10962-7. doi: 10.1073/pnas.1605731113. Epub 2016 Sep 12.


The development of antisense oligonucleotide therapy is an important advance in the identification of corrective therapy for neuromuscular diseases, such as spinal muscular atrophy (SMA). Because of difficulties of delivering single-stranded oligonucleotides to the CNS, current approaches have been restricted to using invasive intrathecal single-stranded oligonucleotide delivery. Here, we report an advanced peptide-oligonucleotide, Pip6a-morpholino phosphorodiamidate oligomer (PMO), which demonstrates potent efficacy in both the CNS and peripheral tissues in severe SMA mice following systemic administration. SMA results from reduced levels of the ubiquitously expressed survival motor neuron (SMN) protein because of loss-of-function mutations in the SMN1 gene. Therapeutic splice-switching oligonucleotides (SSOs) modulate exon 7 splicing of the nearly identical SMN2 gene to generate functional SMN protein. Pip6a-PMO yields SMN expression at high efficiency in peripheral and CNS tissues, resulting in profound phenotypic correction at doses an order-of-magnitude lower than required by standard naked SSOs. Survival is dramatically extended from 12 d to a mean of 456 d, with improvement in neuromuscular junction morphology, down-regulation of transcripts related to programmed cell death in the spinal cord, and normalization of circulating insulin-like growth factor 1. The potent systemic efficacy of Pip6a-PMO, targeting both peripheral as well as CNS tissues, demonstrates the high clinical potential of peptide-PMO therapy for SMA.

Keywords: antisense oligonucleotide; cell-penetrating peptide; spinal muscular atrophy; splice switching oligonucleotide; survival motor neuron.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging
  • Alleles
  • Amino Acid Sequence
  • Biomarkers / blood
  • Cell Line
  • Humans
  • Movement
  • Muscular Atrophy, Spinal / blood
  • Muscular Atrophy, Spinal / drug therapy*
  • Muscular Atrophy, Spinal / pathology
  • Neuromuscular Junction / drug effects
  • Neuromuscular Junction / metabolism
  • Oligonucleotides / administration & dosage
  • Oligonucleotides / pharmacology
  • Oligonucleotides / therapeutic use*
  • Peptides / chemistry*
  • Phenotype
  • RNA Splicing / genetics
  • Survival Analysis
  • Survival of Motor Neuron 2 Protein / genetics


  • Biomarkers
  • Oligonucleotides
  • Peptides
  • Survival of Motor Neuron 2 Protein