A system for small-molecule control of conditionally replication-competent adenoviral vectors

Heung Chong, Anja Ruchatz, Tim Clackson, Victor M. Rivera, Richard Geoffrey Vile

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Replication-competent adenoviral vectors are potentially far more efficient than replication-defective vectors. However, for reasons of safety, there is a need to restrict viral replication both spatially, by limiting replication to certain cell types, and temporally. To control replication temporally, we have developed a system, based on the small-molecule dimerizer rapamycin, for regulating the replication of adenoviral vectors. In this system, one adenoviral vector, AdC4, expresses transcription factors whose activity is regulated by the non-immunosuppressive rapamycin analog AP21967. A second vector, Ad(Z12-I-E1aE1b19k), contains E1 genes placed downstream of binding sites for the regulated transcription factor. Co-infection of several cell lines by the vector pair leads to dimerizer-dependent E1 expression and an increase in viral replication, as shown by Southern blots and replication assays. Furthermore, expression of a reporter gene from a replication-defective vector, Ad-GM-CSF, can be augmented by up to 18-fold by co-infection with the pair of conditionally replicating vectors in the presence of dimerizer. Similar results are obtained when the vectors are directly injected into subcutaneous HT1080 xenograft tumors in nude mice. We believe that vectors based on this principle will be a useful additional tool to enhance efficiency and safety of gene delivery for anti-cancer therapy.

Original languageEnglish (US)
Pages (from-to)195-203
Number of pages9
JournalMolecular Therapy
Volume5
Issue number2
DOIs
StatePublished - 2002

Fingerprint

Sirolimus
Coinfection
Transcription Factors
Safety
Granulocyte-Macrophage Colony-Stimulating Factor
Southern Blotting
Reporter Genes
Heterografts
Nude Mice
Genes
Neoplasms
Binding Sites
Cell Line
Therapeutics
AP 21967

Keywords

  • Adenovirus
  • Gene transfer
  • Inducible
  • Rapamycin
  • Replication-competent virus
  • Vector

ASJC Scopus subject areas

  • Molecular Biology

Cite this

A system for small-molecule control of conditionally replication-competent adenoviral vectors. / Chong, Heung; Ruchatz, Anja; Clackson, Tim; Rivera, Victor M.; Vile, Richard Geoffrey.

In: Molecular Therapy, Vol. 5, No. 2, 2002, p. 195-203.

Research output: Contribution to journalArticle

Chong, Heung ; Ruchatz, Anja ; Clackson, Tim ; Rivera, Victor M. ; Vile, Richard Geoffrey. / A system for small-molecule control of conditionally replication-competent adenoviral vectors. In: Molecular Therapy. 2002 ; Vol. 5, No. 2. pp. 195-203.
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