Rescue of the Spinal Muscular Atrophy Phenotype in a Mouse Model by Early Postnatal Delivery of SMN

Nat Biotechnol. 2010 Mar;28(3):271-4. doi: 10.1038/nbt.1610. Epub 2010 Feb 28.

Abstract

Spinal muscular atrophy (SMA), the most common autosomal recessive neurodegenerative disease affecting children, results in impaired motor neuron function. Despite knowledge of the pathogenic role of decreased survival motor neuron (SMN) protein levels, efforts to increase SMN have not resulted in a treatment for patients. We recently demonstrated that self-complementary adeno-associated virus 9 (scAAV9) can infect approximately 60% of motor neurons when injected intravenously into neonatal mice. Here we use scAAV9-mediated postnatal day 1 vascular gene delivery to replace SMN in SMA pups and rescue motor function, neuromuscular physiology and life span. Treatment on postnatal day 5 results in partial correction, whereas postnatal day 10 treatment has little effect, suggesting a developmental period in which scAAV9 therapy has maximal benefit. Notably, we also show extensive scAAV9-mediated motor neuron transduction after injection into a newborn cynomolgus macaque. This demonstration that scAAV9 traverses the blood-brain barrier in a nonhuman primate emphasizes the clinical potential of scAAV9 gene therapy for SMA.

Publication types

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

MeSH terms

  • Animals
  • Animals, Newborn
  • Dependovirus / genetics
  • Disease Models, Animal
  • Gene Transfer Techniques*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Kaplan-Meier Estimate
  • Macaca fascicularis
  • Male
  • Mice
  • Mice, Transgenic
  • Microscopy, Fluorescence
  • Motor Neurons / metabolism*
  • Muscular Atrophy, Spinal / genetics
  • Muscular Atrophy, Spinal / metabolism
  • Muscular Atrophy, Spinal / therapy*
  • Phenotype
  • Survival of Motor Neuron 1 Protein / biosynthesis*
  • Survival of Motor Neuron 1 Protein / genetics*
  • Survival of Motor Neuron 1 Protein / metabolism

Substances

  • Smn1 protein, mouse
  • Survival of Motor Neuron 1 Protein
  • Green Fluorescent Proteins