Tissue-specific transcriptional targeting of a replication-competent retroviral vector

Christopher R. Logg, Aki Logg, Robert J. Matusik, Bernard H. Bochner, Noriyuki Kasahara

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

The inability of replication-defective viral vectors to efficiently transduce tumor cells in vivo has prevented the successful application of such vectors in gene therapy of cancer. To address the need for more efficient gene delivery systems, we have developed replication-competent retroviral (RCR) vectors based on murine leukemia virus (MLV). We have previously shown that such vectors are capable of transducing solid tumors in vivo with very high efficiency. While the natural requirement of MLV infection for cell division imparts a certain degree of specificity for tumor cells, additional means for confining RCR vector replication to tumor cells are desirable. Here, we investigated the parameters critical for successful tissue-specific transcriptional control of RCR vector replication by replacing various lengths of the MLV enhancer/promoter with sequences derived either from the highly prostate-specific probasin (PB) promoter or from a more potent synthetic variant of the PB promoter. We assessed the transcriptional specificity of the resulting hybrid long terminal repeats (LTRs) and the cell type specificity and efficiency of replication of vectors containing these LTRs. Incorporation of PB promoter sequences effectively restricted transcription from the LTR to prostate-derived cells and imparted prostate-specific RCR vector replication but required the stronger synthetic promoter and retention of native MLV sequences in the vicinity of the TATA box for optimal replicative efficiency and specificity. Our results have thus identified promoter strength and positioning within the LTR as important determinants for achieving both high transduction efficiency and strict cell type specificity in transcriptionally targeted RCR vectors.

Original languageEnglish (US)
Pages (from-to)12783-12791
Number of pages9
JournalJournal of Virology
Volume76
Issue number24
DOIs
StatePublished - Dec 2002
Externally publishedYes

Fingerprint

retroviral vectors
Murine leukemia virus
Murine Leukemia Viruses
terminal repeat sequences
Terminal Repeat Sequences
promoter regions
Prostate
Neoplasms
TATA box
Gene Transfer Techniques
TATA Box
neoplasms
gene therapy
Virus Diseases
cells
virus replication
gene transfer
Genetic Therapy
Cell Division
tissues

ASJC Scopus subject areas

  • Immunology

Cite this

Tissue-specific transcriptional targeting of a replication-competent retroviral vector. / Logg, Christopher R.; Logg, Aki; Matusik, Robert J.; Bochner, Bernard H.; Kasahara, Noriyuki.

In: Journal of Virology, Vol. 76, No. 24, 12.2002, p. 12783-12791.

Research output: Contribution to journalArticle

Logg, Christopher R. ; Logg, Aki ; Matusik, Robert J. ; Bochner, Bernard H. ; Kasahara, Noriyuki. / Tissue-specific transcriptional targeting of a replication-competent retroviral vector. In: Journal of Virology. 2002 ; Vol. 76, No. 24. pp. 12783-12791.
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