| First Author | Xie Q | Year | 2024 |
| Journal | EMBO Mol Med | Volume | 16 |
| Issue | 4 | Pages | 945-965 |
| PubMed ID | 38413838 | Mgi Jnum | J:347664 |
| Mgi Id | MGI:7622330 | Doi | 10.1038/s44321-024-00037-x |
| Citation | Xie Q, et al. (2024) Improved gene therapy for spinal muscular atrophy in mice using codon-optimized hSMN1 transgene and hSMN1 gene-derived promotor. EMBO Mol Med 16(4):945-965 |
| abstractText | Physiological regulation of transgene expression is a major challenge in gene therapy. Onasemnogene abeparvovec (Zolgensma((R))) 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 beta-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. |
