Tissue-specific transcriptional targeting of a replication-competent retroviral vector Journal Article
| Authors: | Logg, C. R.; Logg, A.; Matusik, R. J.; Bochner, B. H.; Kasahara, N. |
| Article Title: | Tissue-specific transcriptional targeting of a replication-competent retroviral vector |
| 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. |
| Keywords: | controlled study; gene sequence; human cell; promoter region; sequence analysis; nonhuman; solid tumor; animal cell; animals; gene targeting; cell division; in vivo study; transcription, genetic; tumor cells, cultured; cancer therapy; cell type; viral gene delivery system; genetic transduction; genetic vectors; prostate; transcription regulation; rat; tumor cell; organ specificity; retrovirus vector; dna, viral; rats; virus replication; long terminal repeat; enhancer region; gene replication; androgen-binding protein; murine leukemia virus; leukemia virus, murine; terminal repeat sequences; humans; human; male; female; priority journal; article; proviruses |
| Journal Title: | Journal of Virology |
| Volume: | 76 |
| Issue: | 24 |
| ISSN: | 0022-538X |
| Publisher: | American Society for Microbiology |
| Date Published: | 2002-12-01 |
| Start Page: | 12783 |
| End Page: | 12791 |
| Language: | English |
| DOI: | 10.1128/jvi.76.24.12783-12791.2002 |
| PUBMED: | 12438603 |
| PROVIDER: | scopus |
| PMCID: | PMC136666 |
| DOI/URL: | |
| Notes: | Export Date: 14 November 2014 -- Source: Scopus |
