Enhanced expression of the human Survival motor neuron 1 gene from a codon-optimised cDNA transgene in vitro and in vivo.
Journal
Gene therapy
ISSN: 1476-5462
Titre abrégé: Gene Ther
Pays: England
ID NLM: 9421525
Informations de publication
Date de publication:
15 Jun 2023
15 Jun 2023
Historique:
received:
20
04
2022
accepted:
04
05
2023
revised:
14
04
2023
medline:
16
6
2023
pubmed:
16
6
2023
entrez:
15
6
2023
Statut:
aheadofprint
Résumé
Spinal muscular atrophy (SMA) is a neuromuscular disease particularly characterised by degeneration of ventral motor neurons. Survival motor neuron (SMN) 1 gene mutations cause SMA, and gene addition strategies to replace the faulty SMN1 copy are a therapeutic option. We have developed a novel, codon-optimised hSMN1 transgene and produced integration-proficient and integration-deficient lentiviral vectors with cytomegalovirus (CMV), human synapsin (hSYN) or human phosphoglycerate kinase (hPGK) promoters to determine the optimal expression cassette configuration. Integrating, CMV-driven and codon-optimised hSMN1 lentiviral vectors resulted in the highest production of functional SMN protein in vitro. Integration-deficient lentiviral vectors also led to significant expression of the optimised transgene and are expected to be safer than integrating vectors. Lentiviral delivery in culture led to activation of the DNA damage response, in particular elevating levels of phosphorylated ataxia telangiectasia mutated (pATM) and γH2AX, but the optimised hSMN1 transgene showed some protective effects. Neonatal delivery of adeno-associated viral vector (AAV9) vector encoding the optimised transgene to the Smn
Identifiants
pubmed: 37322133
doi: 10.1038/s41434-023-00406-0
pii: 10.1038/s41434-023-00406-0
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Spinal Muscular Atrophy Trust (SMA Trust)
ID : UK SMA Research Consortium
Organisme : SMA Trust (Spinal Muscular Atrophy Trust)
ID : UK SMA Research Consortium
Organisme : SMA Trust (Spinal Muscular Atrophy Trust)
ID : UK SMA Research Consortium
Organisme : Great Ormond Street Hospital Charity (GOSH)
ID : V5018
Organisme : Great Ormond Street Hospital Charity (GOSH)
ID : V5018
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature Limited.
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