Engineered HSV vector achieves safe long-term transgene expression in the central nervous system

Abstract Previously we reported a new series of highly defective herpes simplex virus type 1 (HSV-1) vectors that were functionally devoid of all viral immediately early (IE) genes, resulting in virtual absence of viral gene expression. Nevertheless, a reporter gene cassette inserted into the vector...

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Autores principales:	Gianluca Verlengia, Yoshitaka Miyagawa, Selene Ingusci, Justus B. Cohen, Michele Simonato, Joseph C. Glorioso
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/b1d3758c4d1a4cf094352f0ec281ebd2
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spelling	oai:doaj.org-article:b1d3758c4d1a4cf094352f0ec281ebd22021-12-02T11:40:52ZEngineered HSV vector achieves safe long-term transgene expression in the central nervous system10.1038/s41598-017-01635-12045-2322https://doaj.org/article/b1d3758c4d1a4cf094352f0ec281ebd22017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01635-1https://doaj.org/toc/2045-2322Abstract Previously we reported a new series of highly defective herpes simplex virus type 1 (HSV-1) vectors that were functionally devoid of all viral immediately early (IE) genes, resulting in virtual absence of viral gene expression. Nevertheless, a reporter gene cassette inserted into the vector flanked by boundary elements from the viral latency locus showed high, persistent reporter gene activity in non-neuronal cells while an independent expression cassette inserted into a deleted ICP4 locus remained almost silent. In contrast to non-neuronal cells, we show here that the ICP4 locus cassette permitted robust reporter gene expression in a diversity of neurons following stereotactic injection of different rat brain regions; transgene expression in the hippocampus lasted up to 6 months and was essentially restricted to neurons. No evidence of neuronal cell toxicity or induction of inflammatory cell infiltrates was observed. An independent reporter gene cassette located in an intergenic region remained silent, indicating that the transgene promoter and/or insertion site are critical for sustained expression. These findings suggest the suitability of this vector for therapeutic intervention into diseases of the central nervous system that require the expression of large and/or multiple therapeutic transgenes.Gianluca VerlengiaYoshitaka MiyagawaSelene IngusciJustus B. CohenMichele SimonatoJoseph C. GloriosoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Gianluca Verlengia Yoshitaka Miyagawa Selene Ingusci Justus B. Cohen Michele Simonato Joseph C. Glorioso Engineered HSV vector achieves safe long-term transgene expression in the central nervous system
description	Abstract Previously we reported a new series of highly defective herpes simplex virus type 1 (HSV-1) vectors that were functionally devoid of all viral immediately early (IE) genes, resulting in virtual absence of viral gene expression. Nevertheless, a reporter gene cassette inserted into the vector flanked by boundary elements from the viral latency locus showed high, persistent reporter gene activity in non-neuronal cells while an independent expression cassette inserted into a deleted ICP4 locus remained almost silent. In contrast to non-neuronal cells, we show here that the ICP4 locus cassette permitted robust reporter gene expression in a diversity of neurons following stereotactic injection of different rat brain regions; transgene expression in the hippocampus lasted up to 6 months and was essentially restricted to neurons. No evidence of neuronal cell toxicity or induction of inflammatory cell infiltrates was observed. An independent reporter gene cassette located in an intergenic region remained silent, indicating that the transgene promoter and/or insertion site are critical for sustained expression. These findings suggest the suitability of this vector for therapeutic intervention into diseases of the central nervous system that require the expression of large and/or multiple therapeutic transgenes.
format	article
author	Gianluca Verlengia Yoshitaka Miyagawa Selene Ingusci Justus B. Cohen Michele Simonato Joseph C. Glorioso
author_facet	Gianluca Verlengia Yoshitaka Miyagawa Selene Ingusci Justus B. Cohen Michele Simonato Joseph C. Glorioso
author_sort	Gianluca Verlengia
title	Engineered HSV vector achieves safe long-term transgene expression in the central nervous system
title_short	Engineered HSV vector achieves safe long-term transgene expression in the central nervous system
title_full	Engineered HSV vector achieves safe long-term transgene expression in the central nervous system
title_fullStr	Engineered HSV vector achieves safe long-term transgene expression in the central nervous system
title_full_unstemmed	Engineered HSV vector achieves safe long-term transgene expression in the central nervous system
title_sort	engineered hsv vector achieves safe long-term transgene expression in the central nervous system
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/b1d3758c4d1a4cf094352f0ec281ebd2
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Engineered HSV vector achieves safe long-term transgene expression in the central nervous system

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