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Engineering HSV-1 Vectors for Gene Therapy

  • William F. GoinsEmail author
  • Shaohua Huang
  • Justus B. Cohen
  • Joseph C. Glorioso
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1144)

Abstract

Virus vectors have been employed as gene transfer vehicles for various preclinical and clinical gene therapy applications, and with the approval of Glybera (alipogene tiparvovec) as the first gene therapy product as a standard medical treatment (Yla-Herttuala, Mol Ther 20: 1831–1832, 2013), gene therapy has reached the status of being a part of standard patient care. Replication-competent herpes simplex virus (HSV) vectors that replicate specifically in actively dividing tumor cells have been used in Phase I–III human trials in patients with glioblastoma multiforme, a fatal form of brain cancer, and in malignant melanoma. In fact, T-VEC (talimogene laherparepvec, formerly known as OncoVex GM-CSF) displayed efficacy in a recent Phase III trial when compared to standard GM-CSF treatment alone (Andtbacka et al. J Clin Oncol 31: sLBA9008, 2013) and may soon become the second FDA-approved gene therapy product used in standard patient care. In addition to the replication-competent oncolytic HSV vectors like T-VEC, replication-defective HSV vectors have been employed in Phase I–II human trials and have been explored as delivery vehicles for disorders such as pain, neuropathy, and other neurodegenerative conditions. Research during the last decade on the development of HSV vectors has resulted in the engineering of recombinant vectors that are totally replication defective, nontoxic, and capable of long-term transgene expression in neurons. This chapter describes methods for the construction of recombinant genomic HSV vectors based on the HSV-1 replication-defective vector backbones, steps in their purification, and their small-scale production for use in cell culture experiments as well as preclinical animal studies.

Key words

Herpes simplex virus Gene therapy Gene transfer Virus vectors Virus purification Virus production 

Notes

Acknowledgements

This work was supported by NIH grant P01 DK044935 (Glorioso)-Viral Vector Core B (Goins) and P01 CA163205 (Caliguri/Chiocca)-Viral Vector Core B (Goins). We also thank Drs. Krisky, Wolfe, Wechuck, Ozuer, and Kopp for their contribution to HSV vector production and purification methodologies.

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • William F. Goins
    • 1
    Email author
  • Shaohua Huang
    • 1
  • Justus B. Cohen
    • 1
  • Joseph C. Glorioso
    • 1
  1. 1.Department of Microbiology and Molecular Genetics and BiochemistryUniversity of Pittsburgh School of MedicinePittsburghUSA

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