Herpes simplex viral-vector design for efficient transduction of nonneuronal cells without cytotoxicity

Proceedings of the National Academy of Sciences of the United States of America
Yoshitaka MiyagawaJ C Glorioso

Abstract

The design of highly defective herpes simplex virus (HSV) vectors for transgene expression in nonneuronal cells in the absence of toxic viral-gene activity has been elusive. Here, we report that elements of the latency locus protect a nonviral promoter against silencing in primary human cells in the absence of any viral-gene expression. We identified a CTCF motif cluster 5' to the latency promoter and a known long-term regulatory region as important elements for vigorous transgene expression from a vector that is functionally deleted for all five immediate-early genes and the 15-kb internal repeat region. We inserted a 16.5-kb expression cassette for full-length mouse dystrophin and report robust and durable expression in dystrophin-deficient muscle cells in vitro. Given the broad cell tropism of HSV, our design provides a nontoxic vector that can accommodate large transgene constructs for transduction of a wide variety of cells without vector integration, thereby filling an important void in the current arsenal of gene-therapy vectors.

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Citations

Dec 4, 2015·Gene Therapy·J C GloriosoR M Friedlander
May 2, 2016·Experimental Eye Research·Yalong DangNils A Loewen
Jan 10, 2018·Frontiers in Neuroscience·Jean DelbekeDimiter Prodanov
Oct 19, 2017·The Journal of Gene Medicine·Maria VentosaFilip Lim
Dec 13, 2018·Neural Regeneration Research·Hans E Anderson, Richard F Ff Weir
May 6, 2017·Scientific Reports·Gianluca VerlengiaJoseph C Glorioso
Jun 14, 2018·Frontiers in Cellular Neuroscience·Chiara FalcicchiaGianluca Verlengia
Aug 17, 2018·Diseases·Sara ArtusiJoseph C Glorioso
Mar 7, 2019·Epilepsy Currents·Selene IngusciMichele Simonato
Jul 18, 2019·Frontiers in Pharmacology·Selene IngusciMichele Simonato
Feb 12, 2020·Molecular Therapy. Methods & Clinical Development·Ceren TuzmenJoseph C Glorioso
Nov 20, 2020·Experimental Eye Research·Rajiv R MohanNishant R Sinha
Apr 20, 2021·Molecular Therapy. Methods & Clinical Development·Marie SoukupováMichele Simonato
Jun 8, 2021·Virology : Research and Treatment·Prapti H ModyJuliet V Spencer
Apr 18, 2020·Molecular Therapy. Methods & Clinical Development·Seiji KurodaTakashi Okada
Nov 7, 2020·Current Gene Therapy·Md Sahab UddinGhulam Md Ashraf

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