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The FASEB Journal, Vol 7, 971-977, Copyright © 1993 by The Federation of American Societies for Experimental Biology

RESEARCH COMMUNICATIONS

Synthetic retrotransposon vectors for gene therapy

AK Chakraborty, MA Zink, BM Boman and CP Hodgson
Creighton Cancer Center/Dept. of Biomedical Sciences, Creighton School of Medicine, Omaha, Nebraska 68178.

New gene therapy methods are rapidly being developed to permit the expression of tumor suppressor genes, cytotoxins, anticancer antigens, and immunoregulatory proteins in the treatment of cancer. Large-scale testing in humans has been delayed by questions concerning the safety and effectiveness of preferred retroviral vectors and helper cells. These vector systems are limited by their ability to undergo homologous recombination with endogenous retroviruses or helper-viral sequences, resulting in release of replication-competent retrovirus (RCR). In addition, transcriptional inactivation of the retroviral promoter often occurs, caused in part by methylation of CpG islands in the retroviral long terminal repeats (LTRs). We report the production of highly specific retrovectors using gene amplification together with oligonucleotide building blocks. The synthetic vectors were based on mouse VL30 retrotransposon NVL3, and lacked homology to retroviral helper gene sequences. Three of four constructs made by gene amplification yielded biologically active vectors. These constructs efficiently transmitted and stably inserted a neomycin resistance marker gene into the genome of recipient cells, expressing an abundant RNA species of the expected size in the absence of detectable replication competent retrovirus. The vectors and techniques described enable widely applicable expression modes using generic helper cells, and require only approximately 1.3 kb of cis-acting vector RNA sequences for faithful transfer and expression of genetic material.


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M. Lopez-Lastra, S. Ulrici, C. Gabus, and J.-L. Darlix
Identification of an Internal Ribosome Entry Segment in the 5' Region of the Mouse VL30 Retrotransposon and Its Use in the Development of Retroviral Vectors
J. Virol., October 1, 1999; 73(10): 8393 - 8402.
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Copyright © 1993 by The Federation of American Societies for Experimental Biology.