Intra-articular delivery of a herpes simplex virus IL-1Ra gene vector reduces inflammation in a rabbit model of arthritis

T. Oligino, S. C. Ghivizzani, D. Wolfe, E. R. Lechman, D. Krisky, Z. Mi, C. H. Evans, P. D. Robbins, J. C. Glorioso

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

Abstract

To evaluate the use of HSV-based vectors for arthritis gene therapy we have constructed a first-generation, ICP4 deficient, replication defective herpes simplex virus (HSV) vector (S/O-) and a second-generation HSV vector derivative (T/O-) deficient for the immediate-early genes ICP4, 22 and 27, each carrying a soluble TNF receptor or IL-1 receptor antagonist transgene cassette. A rabbit synovial-fibroblast line in culture, infected by either vector enabled high-level expression of the transgene product. However, following a single intra-articular injection of the vectors into rabbit knee joints, only the second-generation, HSV T/O- vector expressed detectable levels of soluble TNFR in synovial fluid. Synovial lavage fluid from inoculated joints contained up to 12 ng/ml of soluble receptor that persisted at detectable, but reduced levels for at least 7 days. When tested in an experimental model of arthritis generated by intra-articular overexpression of interleukin-1β using retrovirus transduced synovial cells, the HSV T/O- vector expressing the interleukin-1 receptor antagonist was found to inhibit leukocytosis and synovitis significantly. The improved levels and duration of intra-articular transgene expression achieved via HSV-mediated gene delivery suggest that an HSV vector system could be used for therapeutic applications in patients with rheumatoid arthritis (RA) and other joint-related inflammatory diseases.

Original languageEnglish (US)
Pages (from-to)1713-1720
Number of pages8
JournalGene therapy
Volume6
Issue number10
DOIs
StatePublished - Oct 1999
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by National Institute of Health grants NIH-NIAMS-96–1 (PDR) and 5R01 AR44526–02 (JCG).

Keywords

  • Arthritis
  • HSV
  • IL-1Ra
  • sTNFR

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