Comparison of the efficacy of MOE and PMO modifications of systemic antisense oligonucleotides in a severe SMA mouse model

Nucleic Acids Res. 2020 Apr 6;48(6):2853-2865. doi: 10.1093/nar/gkaa126.


Spinal muscular atrophy (SMA) is a motor neuron disease. Nusinersen, a splice-switching antisense oligonucleotide (ASO), was the first approved drug to treat SMA. Based on prior preclinical studies, both 2'-O-methoxyethyl (MOE) with a phosphorothioate backbone and morpholino with a phosphorodiamidate backbone-with the same or extended target sequence as nusinersen-displayed efficient rescue of SMA mouse models. Here, we compared the therapeutic efficacy of these two modification chemistries in rescue of a severe mouse model using ASO10-29-a 2-nt longer version of nusinersen-via subcutaneous injection. Although both chemistries efficiently corrected SMN2 splicing in various tissues, restored motor function and improved the integrity of neuromuscular junctions, MOE-modified ASO10-29 (MOE10-29) was more efficacious than morpholino-modified ASO10-29 (PMO10-29) at the same molar dose, as seen by longer survival, greater body-weight gain and better preservation of motor neurons. Time-course analysis revealed that MOE10-29 had more persistent effects than PMO10-29. On the other hand, PMO10-29 appears to more readily cross an immature blood-brain barrier following systemic administration, showing more robust initial effects on SMN2 exon 7 inclusion, but less persistence in the central nervous system. We conclude that both modifications can be effective as splice-switching ASOs in the context of SMA and potentially other diseases, and discuss the advantages and disadvantages of each.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemistry*
  • Animals
  • Disease Models, Animal
  • Exons / genetics
  • Humans
  • Mice, Transgenic
  • Morpholinos / pharmacology
  • Morpholinos / therapeutic use*
  • Motor Activity / drug effects
  • Motor Neurons / drug effects
  • Motor Neurons / pathology
  • Muscles / pathology
  • Muscular Atrophy, Spinal / drug therapy*
  • Muscular Atrophy, Spinal / pathology
  • Muscular Atrophy, Spinal / physiopathology
  • Neuromuscular Junction / pathology
  • Neuromuscular Junction / physiopathology
  • Oligonucleotides, Antisense / pharmacology
  • Oligonucleotides, Antisense / therapeutic use*
  • Phenotype
  • Phosphoric Acids / chemistry*
  • RNA Splicing / drug effects
  • RNA Splicing / genetics
  • Spinal Cord / pathology
  • Survival of Motor Neuron 2 Protein / genetics
  • Treatment Outcome


  • Amides
  • Morpholinos
  • Oligonucleotides, Antisense
  • Phosphoric Acids
  • SMN2 protein, mouse
  • Survival of Motor Neuron 2 Protein
  • phosphoramidic acid