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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

Gene Therapy volume 30, pages 812–825 (2023)Cite this article

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Abstract

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 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.

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Fig. 1: Maps displaying features of the transfer plasmids encoding Co-hSMN1 or control eGFP.
Fig. 2: Lentiviral vector-mediated hSMN1 and Co-hSMN1 expression in mouse primary cortical neurons and rat primary motor neurons.
Fig. 3: Assessment of SMN protein levels in iPSC motor neurons.
Fig. 4: SMN levels in primary SMA type I patient fibroblasts following IDLV transduction.
Fig. 5: Restoration of gems in SMA type I fibroblasts transduced with lentiviral vectors encoding hSMN1 or Co-hSMN1.
Fig. 6: The effect of IDLV_CMV_Co-hSMN1 transduction on γH2AX foci in SMA type I fibroblasts.
Fig. 7: ATM and pATM in wild-type and SMA type I fibroblasts and SMA type I iPSC-derived motor neurons.
Fig. 8: Analysis of SMN levels following in vivo neonatal administration of AAV9 vectors expressing Co-hSMN1.

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Data availability

The data generated during this study are available within the published article and its supplementary files, or from the corresponding author on reasonable request.

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Funding

Funding

EMC was partially funded by a scholarship from Royal Holloway University of London. NAMN was partially funded by a scholarship and student stipend, from Royal Holloway University of London and The Spinal Muscular Atrophy Trust. HF acknowledges financial support for SMA research from the Great Ormond Street Hospital Charity (GOSH) which funds SB (Grant No. V5018). RJY-M acknowledges general financial support from SMA UK (formerly The SMA Trust), through the UK SMA Research Consortium, for SMA research in his laboratory. MB acknowledges general financial support from SMA UK, Muscular Dystrophy UK, Action Medical Research, SMA Angels Charity and Academy of Medical Sciences for SMA research in her laboratory.

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Author notes

  1. These authors contributed equally: Neda A. M. Nafchi, Ellie M. Chilcott.

Authors and Affiliations

  1. AGCTlab.org, Centre of Gene and Cell Therapy, Centre for Biomedical Sciences, Department of Biological Sciences, School of Life Sciences and the Environment, Royal Holloway University of London, Egham, TW20 0EX, UK

    Neda A. M. Nafchi, Ellie M. Chilcott & Rafael J. Yáñez-Muñoz

  2. School of Pharmacy and Bioengineering, Keele University, Staffordshire, ST5 5BG, UK

    Sharon Brown & Heidi R. Fuller

  3. Wolfson Centre for Inherited Neuromuscular Disease, TORCH Building, RJAH Orthopaedic Hospital, Oswestry, SY10 7AG, UK

    Sharon Brown, Heidi R. Fuller & Melissa Bowerman

  4. School of Medicine, Keele University, Staffordshire, ST5 5BG, UK

    Melissa Bowerman

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Contributions

EMC and NAMN performed in vitro experimentation and analyses. MB performed in vivo injections and tissue harvests whilst SB analysed tissue from in vivo experiments. HF provided support for animal experimentation. RJY-M provided conceptual support and interpretation of results. All authors contributed to manuscript preparation.

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Correspondence to Rafael J. Yáñez-Muñoz.

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NAMN, EMC, and RJY-M have filed a patent application on the uses of the novel SMN transgene reported in this manuscript. SB, HRF, and MB report no conflicts of interest.

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Nafchi, N.A.M., Chilcott, E.M., Brown, S. et al. Enhanced expression of the human Survival motor neuron 1 gene from a codon-optimised cDNA transgene in vitro and in vivo. Gene Ther 30, 812–825 (2023). https://doi.org/10.1038/s41434-023-00406-0

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