AAV9-Mediated Expression of SMN Restricted to Neurons Does Not Rescue the Spinal Muscular Atrophy Phenotype in Mice

Mol Ther. 2020 Aug 5;28(8):1887-1901. doi: 10.1016/j.ymthe.2020.05.011. Epub 2020 May 15.


Spinal muscular atrophy (SMA) is a neuromuscular disease mainly caused by mutations or deletions in the survival of motor neuron 1 (SMN1) gene and characterized by the degeneration of motor neurons and progressive muscle weakness. A viable therapeutic approach for SMA patients is a gene replacement strategy that restores functional SMN expression using adeno-associated virus serotype 9 (AAV9) vectors. Currently, systemic or intra-cerebrospinal fluid (CSF) delivery of AAV9-SMN is being explored in clinical trials. In this study, we show that the postnatal delivery of an AAV9 that expresses SMN under the control of the neuron-specific promoter synapsin selectively targets neurons without inducing re-expression in the peripheral organs of SMA mice. However, this approach is less efficient in restoring the survival and neuromuscular functions of SMA mice than the systemic or intra-CSF delivery of an AAV9 in which SMN is placed under the control of a ubiquitous promoter. This study suggests that further efforts are needed to understand the extent to which SMN is required in neurons and peripheral organs for a successful therapeutic effect.

Keywords: AAV; SMA; SMN; gene therapy; neurons; peripheral organs; spinal muscular atrophy; synapsin promoter; ubiquitous promoter.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dependovirus / genetics*
  • Disease Models, Animal
  • Gene Expression
  • Gene Transfer Techniques
  • Genetic Therapy
  • Genetic Vectors / genetics*
  • Locomotion
  • Mice
  • Motor Neurons / metabolism*
  • Motor Neurons / virology*
  • Muscular Atrophy, Spinal / drug therapy
  • Muscular Atrophy, Spinal / genetics*
  • Phenotype
  • Prognosis
  • Promoter Regions, Genetic
  • Spinal Cord / metabolism
  • Spinal Cord / pathology
  • Survival of Motor Neuron 1 Protein / genetics*
  • Survival of Motor Neuron 1 Protein / metabolism
  • Transduction, Genetic
  • Treatment Outcome


  • Survival of Motor Neuron 1 Protein