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

Author:

Miyagawa Yoshitaka,Marino Pietro,Verlengia Gianluca,Uchida Hiroaki,Goins William F.,Yokota Shinichiro,Geller David A.,Yoshida Osamu,Mester Joseph,Cohen Justus B.,Glorioso Joseph C.

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.

Funder

HHS | NIH | National Institute of Neurological Disorders and Stroke

HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases

CHDI Foundation

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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