Defining the therapeutic window in a severe animal model of spinal muscular atrophy

Hum Mol Genet. 2014 Sep 1;23(17):4559-68. doi: 10.1093/hmg/ddu169. Epub 2014 Apr 9.


Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by the loss of a single gene, Survival Motor Neuron-1 (SMN1). Administration of a self-complementary Adeno-Associated Virus vector expressing full-length SMN cDNA (scAAV-SMN) has proven an effective means to rescue the SMA phenotype in SMA mice, either by intravenous (IV) or intracerebroventricular (ICV) administration at very early time points. We have recently shown that ICV delivery of scAAV9-SMN is more effective than a similar dose of vector administered via an IV injection, thereby providing an important mechanism to examine a timeline for rescuing the disease and determining the therapeutic window in a severe model of SMA. In this report, we utilized a relatively severe mouse model of SMA, SMNΔ7. Animals were injected with scAAV9-SMN vector via ICV injection on a single day, from P2 through P8. At each delivery point from P2 through P8, scAAV9-SMN decreased disease severity. A near complete rescue was obtained following P2 injection while a P8 injection produced a ∼ 40% extension in survival. Analysis of the underlying neuromuscular junction (NMJ) pathology revealed that late-stage delivery of the vector failed to provide protection from NMJ defects despite robust SMN expression in the central nervous system. While our study demonstrates that a maximal benefit is obtained when treatment is delivered during pre-symptomatic stages, significant therapeutic benefit can still be achieved after the onset of disease symptoms.

Publication types

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

MeSH terms

  • Animals
  • Body Weight
  • Chickens
  • Dependovirus / genetics
  • Disease Models, Animal
  • Genetic Therapy
  • Genetic Vectors / administration & dosage
  • HEK293 Cells
  • Humans
  • Injections, Intraventricular
  • Mice
  • Motor Activity
  • Muscle, Skeletal / pathology
  • Muscle, Skeletal / physiopathology
  • Muscular Atrophy, Spinal / pathology
  • Muscular Atrophy, Spinal / physiopathology
  • Muscular Atrophy, Spinal / therapy*
  • Neuromuscular Junction / pathology
  • Neuromuscular Junction / physiopathology
  • Phenotype
  • Survival Analysis
  • Survival of Motor Neuron 1 Protein / genetics
  • Survival of Motor Neuron 1 Protein / therapeutic use
  • Time Factors


  • Survival of Motor Neuron 1 Protein