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Optimized lentiviral vector for restoration of full-length dystrophin via a cell-mediated approach in a mouse model of Duchenne muscular dystrophy

Meng, Jinhong; Moore, Marc; Counsell, John; Muntoni, Francesco; Popplewell, Linda; Morgan, Jennifer; (2022) Optimized lentiviral vector for restoration of full-length dystrophin via a cell-mediated approach in a mouse model of Duchenne muscular dystrophy. Molecular Therapy: Methods & Clinical Development 10.1016/j.omtm.2022.04.015. (In press). Green open access

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Meng_Optimized lentiviral vector for restoration of full-length dystrophin via a cell-mediated approach in a mouse model of Duchenne muscular dystrophy_Pre-proof.pdf - Accepted Version

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Abstract

Duchenne muscular dystrophy (DMD) is a muscle wasting disorder caused by mutations in the DMD gene. Restoration of full-length dystrophin protein in skeletal muscle would have therapeutic benefit, but lentivirally-mediated delivery of such a large gene in vivo has been hindered by lack of tissue-specificity, limited transduction and insufficient transgene expression. To address these problems, we developed a lentiviral vector, which contained a muscle-specific promoter and sequence optimized full-length dystrophin, to constrain the dystrophin expression to differentiated myotubes/myofibres and enhance the transgene expression. We further explored the efficiency of restoration of full-length dystrophin in vivo, by grafting DMD myoblasts that had been corrected by this optimized lentiviral vector intramuscularly into an immunodeficient DMD mouse model. We showed that these lentivirally-corrected DMD myoblasts effectively reconstituted full-length dystrophin expression in 93.58±2.17% of the myotubes in vitro. Moreover, dystrophin was restored in 64.4±2.87% of the donor-derived regenerated muscle fibres in vivo, which was able to recruit members of the dystrophin glycoprotein complex at the sarcolemma. This study represents a significant advance over existing cell-mediated gene therapy strategies for DMD that aim to restore full-length dystrophin expression in skeletal muscle.

Type: Article
Title: Optimized lentiviral vector for restoration of full-length dystrophin via a cell-mediated approach in a mouse model of Duchenne muscular dystrophy
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.omtm.2022.04.015
Publisher version: https://doi.org/10.1016/j.omtm.2022.04.015
Language: English
Additional information: Copyright © 2022 The Author(s). This is an Open Access article published under a Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/).
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Developmental Neurosciences Dept
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10148193
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