Lentiviral vectors can be used for full-length dystrophin gene therapy

Abstract Duchenne Muscular Dystrophy (DMD) is caused by a lack of dystrophin expression in patient muscle fibres. Current DMD gene therapy strategies rely on the expression of internally deleted forms of dystrophin, missing important functional domains. Viral gene transfer of full-length dystrophin...

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Autores principales:	John R. Counsell, Zeinab Asgarian, Jinhong Meng, Veronica Ferrer, Conrad A. Vink, Steven J. Howe, Simon N. Waddington, Adrian J. Thrasher, Francesco Muntoni, Jennifer E. Morgan, Olivier Danos
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a4e4bc5af0674a76abc106a806bbacbb
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spelling	oai:doaj.org-article:a4e4bc5af0674a76abc106a806bbacbb2021-12-02T12:30:18ZLentiviral vectors can be used for full-length dystrophin gene therapy10.1038/s41598-017-00152-52045-2322https://doaj.org/article/a4e4bc5af0674a76abc106a806bbacbb2017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00152-5https://doaj.org/toc/2045-2322Abstract Duchenne Muscular Dystrophy (DMD) is caused by a lack of dystrophin expression in patient muscle fibres. Current DMD gene therapy strategies rely on the expression of internally deleted forms of dystrophin, missing important functional domains. Viral gene transfer of full-length dystrophin could restore wild-type functionality, although this approach is restricted by the limited capacity of recombinant viral vectors. Lentiviral vectors can package larger transgenes than adeno-associated viruses, yet lentiviral vectors remain largely unexplored for full-length dystrophin delivery. In our work, we have demonstrated that lentiviral vectors can package and deliver inserts of a similar size to dystrophin. We report a novel approach for delivering large transgenes in lentiviruses, in which we demonstrate proof-of-concept for a ‘template-switching’ lentiviral vector that harnesses recombination events during reverse-transcription. During this work, we discovered that a standard, unmodified lentiviral vector was efficient in delivering full-length dystrophin to target cells, within a total genomic load of more than 15,000 base pairs. We have demonstrated gene therapy with this vector by restoring dystrophin expression in DMD myoblasts, where dystrophin was expressed at the sarcolemma of myotubes after myogenic differentiation. Ultimately, our work demonstrates proof-of-concept that lentiviruses can be used for permanent full-length dystrophin gene therapy, which presents a significant advancement in developing an effective treatment for DMD.John R. CounsellZeinab AsgarianJinhong MengVeronica FerrerConrad A. VinkSteven J. HoweSimon N. WaddingtonAdrian J. ThrasherFrancesco MuntoniJennifer E. MorganOlivier DanosNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-10 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q John R. Counsell Zeinab Asgarian Jinhong Meng Veronica Ferrer Conrad A. Vink Steven J. Howe Simon N. Waddington Adrian J. Thrasher Francesco Muntoni Jennifer E. Morgan Olivier Danos Lentiviral vectors can be used for full-length dystrophin gene therapy
description	Abstract Duchenne Muscular Dystrophy (DMD) is caused by a lack of dystrophin expression in patient muscle fibres. Current DMD gene therapy strategies rely on the expression of internally deleted forms of dystrophin, missing important functional domains. Viral gene transfer of full-length dystrophin could restore wild-type functionality, although this approach is restricted by the limited capacity of recombinant viral vectors. Lentiviral vectors can package larger transgenes than adeno-associated viruses, yet lentiviral vectors remain largely unexplored for full-length dystrophin delivery. In our work, we have demonstrated that lentiviral vectors can package and deliver inserts of a similar size to dystrophin. We report a novel approach for delivering large transgenes in lentiviruses, in which we demonstrate proof-of-concept for a ‘template-switching’ lentiviral vector that harnesses recombination events during reverse-transcription. During this work, we discovered that a standard, unmodified lentiviral vector was efficient in delivering full-length dystrophin to target cells, within a total genomic load of more than 15,000 base pairs. We have demonstrated gene therapy with this vector by restoring dystrophin expression in DMD myoblasts, where dystrophin was expressed at the sarcolemma of myotubes after myogenic differentiation. Ultimately, our work demonstrates proof-of-concept that lentiviruses can be used for permanent full-length dystrophin gene therapy, which presents a significant advancement in developing an effective treatment for DMD.
format	article
author	John R. Counsell Zeinab Asgarian Jinhong Meng Veronica Ferrer Conrad A. Vink Steven J. Howe Simon N. Waddington Adrian J. Thrasher Francesco Muntoni Jennifer E. Morgan Olivier Danos
author_facet	John R. Counsell Zeinab Asgarian Jinhong Meng Veronica Ferrer Conrad A. Vink Steven J. Howe Simon N. Waddington Adrian J. Thrasher Francesco Muntoni Jennifer E. Morgan Olivier Danos
author_sort	John R. Counsell
title	Lentiviral vectors can be used for full-length dystrophin gene therapy
title_short	Lentiviral vectors can be used for full-length dystrophin gene therapy
title_full	Lentiviral vectors can be used for full-length dystrophin gene therapy
title_fullStr	Lentiviral vectors can be used for full-length dystrophin gene therapy
title_full_unstemmed	Lentiviral vectors can be used for full-length dystrophin gene therapy
title_sort	lentiviral vectors can be used for full-length dystrophin gene therapy
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/a4e4bc5af0674a76abc106a806bbacbb
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Lentiviral vectors can be used for full-length dystrophin gene therapy

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