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Enhanced expression of the human Survival motor neuron 1 gene from a codon-optimised cDNA transgene in vitro and in vivo

Nafchi, NAM; Chilcott, EM; Brown, SJ; Fuller, H; Bowerman, M; Yáñez-Muñoz, RJ


NAM Nafchi

EM Chilcott

SJ Brown

RJ Yáñez-Muñoz


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 ?H2AX, but the optimised hSMN1 transgene showed some protective effects. Neonatal delivery of adeno-associated viral vector (AAV9) vector encoding the optimised transgene to the Smn2B/- mouse model of SMA resulted in a significant increase of SMN protein levels in liver and spinal cord. This work shows the potential of a novel codon-optimised hSMN1 transgene as a therapeutic strategy for SMA.


Nafchi, N., Chilcott, E., Brown, S., Fuller, H., Bowerman, M., & Yáñez-Muñoz, R. (2023). Enhanced expression of the human Survival motor neuron 1 gene from a codon-optimised cDNA transgene in vitro and in vivo. Gene Therapy,

Acceptance Date Apr 13, 2023
Online Publication Date Jun 15, 2023
Publication Date Jun 15, 2023
Publicly Available Date Jun 16, 2024
Journal Gene Therapy (Basingstoke)
Print ISSN 0969-7128
Electronic ISSN 1476-5462
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Keywords DNA damage and repair; Gene expression; Gene expression analysis; Genetic vectors; Targeted gene repair