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Autologous skeletal muscle derived cells expressing a novel functional dystrophin provide a potential therapy for Duchenne Muscular Dystrophy.
Sci Rep. 2016 Jan 27; 6:19750.SR

Abstract

Autologous stem cells that have been genetically modified to express dystrophin are a possible means of treating Duchenne Muscular Dystrophy (DMD). To maximize the therapeutic effect, dystrophin construct needs to contain as many functional motifs as possible, within the packaging capacity of the viral vector. Existing dystrophin constructs used for transduction of muscle stem cells do not contain the nNOS binding site, an important functional motif within the dystrophin gene. In this proof-of-concept study, using stem cells derived from skeletal muscle of a DMD patient (mdcs) transplanted into an immunodeficient mouse model of DMD, we report that two novel dystrophin constructs, C1 (ΔR3-R13) and C2 (ΔH2-R23), can be lentivirally transduced into mdcs and produce dystrophin. These dystrophin proteins were functional in vivo, as members of the dystrophin glycoprotein complex were restored in muscle fibres containing donor-derived dystrophin. In muscle fibres derived from cells that had been transduced with construct C1, the largest dystrophin construct packaged into a lentiviral system, nNOS was restored. The combination of autologous stem cells and a lentivirus expressing a novel dystrophin construct which optimally restores proteins of the dystrophin glycoprotein complex may have therapeutic application for all DMD patients, regardless of their dystrophin mutation.

Authors+Show Affiliations

The Dubowitz Neuromuscular Centre, Molecular Neurosciences Section, Developmental Neurosciences Programme, UCL Institute of Child Health, 30 Guilford Street, London, UK, WC1N 1EH.The Dubowitz Neuromuscular Centre, Molecular Neurosciences Section, Developmental Neurosciences Programme, UCL Institute of Child Health, 30 Guilford Street, London, UK, WC1N 1EH. UCL Cancer Institute, Paul O'Gorman Building, University College London, 72 Huntley Street, London, UK, WC1E 6BT. Molecular and Cellular Immunology, Institute of Child Health, University College London, 30 Guilford Street, London, UK, WC1N 1EH.John Walton Centre for Muscular Dystrophy Research, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK, NE1 3BZ.John Walton Centre for Muscular Dystrophy Research, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK, NE1 3BZ.UCL Cancer Institute, Paul O'Gorman Building, University College London, 72 Huntley Street, London, UK, WC1E 6BT.Molecular and Cellular Immunology, Institute of Child Health, University College London, 30 Guilford Street, London, UK, WC1N 1EH.John Walton Centre for Muscular Dystrophy Research, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK, NE1 3BZ.The Dubowitz Neuromuscular Centre, Molecular Neurosciences Section, Developmental Neurosciences Programme, UCL Institute of Child Health, 30 Guilford Street, London, UK, WC1N 1EH.The Dubowitz Neuromuscular Centre, Molecular Neurosciences Section, Developmental Neurosciences Programme, UCL Institute of Child Health, 30 Guilford Street, London, UK, WC1N 1EH.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26813695

Citation

Meng, Jinhong, et al. "Autologous Skeletal Muscle Derived Cells Expressing a Novel Functional Dystrophin Provide a Potential Therapy for Duchenne Muscular Dystrophy." Scientific Reports, vol. 6, 2016, p. 19750.
Meng J, Counsell JR, Reza M, et al. Autologous skeletal muscle derived cells expressing a novel functional dystrophin provide a potential therapy for Duchenne Muscular Dystrophy. Sci Rep. 2016;6:19750.
Meng, J., Counsell, J. R., Reza, M., Laval, S. H., Danos, O., Thrasher, A., Lochmüller, H., Muntoni, F., & Morgan, J. E. (2016). Autologous skeletal muscle derived cells expressing a novel functional dystrophin provide a potential therapy for Duchenne Muscular Dystrophy. Scientific Reports, 6, 19750. https://doi.org/10.1038/srep19750
Meng J, et al. Autologous Skeletal Muscle Derived Cells Expressing a Novel Functional Dystrophin Provide a Potential Therapy for Duchenne Muscular Dystrophy. Sci Rep. 2016 Jan 27;6:19750. PubMed PMID: 26813695.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Autologous skeletal muscle derived cells expressing a novel functional dystrophin provide a potential therapy for Duchenne Muscular Dystrophy. AU - Meng,Jinhong, AU - Counsell,John R, AU - Reza,Mojgan, AU - Laval,Steven H, AU - Danos,Olivier, AU - Thrasher,Adrian, AU - Lochmüller,Hanns, AU - Muntoni,Francesco, AU - Morgan,Jennifer E, Y1 - 2016/01/27/ PY - 2015/09/22/received PY - 2015/12/17/accepted PY - 2016/1/28/entrez PY - 2016/1/28/pubmed PY - 2017/1/7/medline SP - 19750 EP - 19750 JF - Scientific reports JO - Sci Rep VL - 6 N2 - Autologous stem cells that have been genetically modified to express dystrophin are a possible means of treating Duchenne Muscular Dystrophy (DMD). To maximize the therapeutic effect, dystrophin construct needs to contain as many functional motifs as possible, within the packaging capacity of the viral vector. Existing dystrophin constructs used for transduction of muscle stem cells do not contain the nNOS binding site, an important functional motif within the dystrophin gene. In this proof-of-concept study, using stem cells derived from skeletal muscle of a DMD patient (mdcs) transplanted into an immunodeficient mouse model of DMD, we report that two novel dystrophin constructs, C1 (ΔR3-R13) and C2 (ΔH2-R23), can be lentivirally transduced into mdcs and produce dystrophin. These dystrophin proteins were functional in vivo, as members of the dystrophin glycoprotein complex were restored in muscle fibres containing donor-derived dystrophin. In muscle fibres derived from cells that had been transduced with construct C1, the largest dystrophin construct packaged into a lentiviral system, nNOS was restored. The combination of autologous stem cells and a lentivirus expressing a novel dystrophin construct which optimally restores proteins of the dystrophin glycoprotein complex may have therapeutic application for all DMD patients, regardless of their dystrophin mutation. SN - 2045-2322 UR - https://www.unboundmedicine.com/medline/citation/26813695/Autologous_skeletal_muscle_derived_cells_expressing_a_novel_functional_dystrophin_provide_a_potential_therapy_for_Duchenne_Muscular_Dystrophy_ L2 - http://dx.doi.org/10.1038/srep19750 DB - PRIME DP - Unbound Medicine ER -