Improved gene therapy for spinal muscular atrophy in mice using codon-optimized hSMN1 transgene and hSMN1 gene-derived promotor

EMBO Mol Med. 2024 Apr;16(4):945-965. doi: 10.1038/s44321-024-00037-x. Epub 2024 Feb 27.


Physiological regulation of transgene expression is a major challenge in gene therapy. Onasemnogene abeparvovec (Zolgensma®) is an approved adeno-associated virus (AAV) vector gene therapy for infants with spinal muscular atrophy (SMA), however, adverse events have been observed in both animals and patients following treatment. The construct contains a native human survival motor neuron 1 (hSMN1) transgene driven by a strong, cytomegalovirus enhancer/chicken β-actin (CMVen/CB) promoter providing high, ubiquitous tissue expression of SMN. We developed a second-generation AAV9 gene therapy expressing a codon-optimized hSMN1 transgene driven by a promoter derived from the native hSMN1 gene. This vector restored SMN expression close to physiological levels in the central nervous system and major systemic organs of a severe SMA mouse model. In a head-to-head comparison between the second-generation vector and a benchmark vector, identical in design to onasemnogene abeparvovec, the 2nd-generation vector showed better safety and improved efficacy in SMA mouse model.

Keywords: AAV; Endogenous Promoter; Gene Therapy; SMA; SMN1.

MeSH terms

  • Animals
  • Disease Models, Animal
  • Genetic Therapy
  • Humans
  • Infant
  • Mice
  • Motor Neurons / metabolism
  • Muscular Atrophy, Spinal* / genetics
  • Muscular Atrophy, Spinal* / therapy
  • Promoter Regions, Genetic
  • Transgenes