Herpesvirus-mediated systemic delivery of nerve growth factor

Darren Wolfe, William F. Goins, Theodore J. Kaplan, Saverio V. Capuano, Julie Fradette, Michael Murphey-Corb, Paul D. Robbins, Justus B. Cohen, Joseph C. Glorioso

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

Sustained systemic dissemination of therapeutic proteins from peripheral sites is an attractive prospect for gene therapy applications. Replication-defective genomic herpes simplex virus type 1 (HSV-1) vectors were evaluated for their ability to express nerve growth factor (NGF) as a model gene product both locally and systemically. Intra-articular inoculation of NGF expression vectors in rabbits resulted in significant increases in joint lavage and blood plasma NGF that persisted for 1 year. A rhesus macaque injected intra-articularly displayed a comparable increase in plasma NGF for at least 6 months, at which time the serum NGF levels of this animal were sufficient to cause differentiation of PC12 cells in culture, but not to increase footpad epidermis innervation. Long-term reporter transgene expression was observed primarily in ligaments, a finding confirmed by direct inoculation of patellar ligament. Patellar ligament inoculation with a NGF vector resulted in elevated levels of circulating NGF similar to those observed following intra-articular vector delivery. These results represent the first demonstration of sustained systemic release of a transgene product using HSV vectors, raising the prospect of new applications for HSV-1 vectors in the treatment of systemic disease.

Original languageEnglish (US)
Pages (from-to)61-69
Number of pages9
JournalMolecular Therapy
Volume3
Issue number1
DOIs
StatePublished - 2001
Externally publishedYes

Bibliographical note

Funding Information:
We thank Neal DeLuca for providing the ICP4 mutant d120 and the ICP4 complementing cell line E5. We thank Ali Ozuer, Steve Ghivizzani, Melanie Osborn, and Dawn McClemens for excellent technical support. This work was supported by Public Health Service Grants AR44526, GM34534, and DK44935 to J.C.G., NS38850 to J.C.G., and NIAMS-96-1 to P.D.R.

Keywords

  • Gene therapy
  • HSV vector
  • Intra-articular
  • NGF
  • Patellar ligament

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