Plasmoviruses: nonviral/viral vectors for gene therapy.

Important note: Information in this article was accurate in 1996. The state of the art may have changed since the publication date.

Plasmoviruses: nonviral/viral vectors for gene therapy.

Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4175-80. Unique Identifier : AIDSLINE MED/96210613
Noguiez-Hellin P; Meur MR; Salzmann JL; Klatzmann D; Genopoietic, Paris, France.

Abstract: We have generated a chimeric gene transfer vector that combines the simplicity of plasmids with the infectivity and long-term expression of retroviruses. We replaced the env gene of a Moloney murine leukemia virus-derived provirus by a foreign gene, generating a plasmid that upon transfer to tumor cells generates noninfectious retroviral particles carrying the transgene. We added to this plasmid an independent expression cassette comprising a cytomegalovirus promoter, an amphotropic retroviral envelope, and a polyadenylylation signal from simian virus 40. These constructs were designed to minimize the risk of recombination generating replication-competent retroviruses. Their only region of homology is a 157-bp sequence with 53% identity. We show that the sole transfection of this plasmid in various cell lines generates infectious but defective retroviral particles capable of efficiently infecting and expressing the transgene. The formation of infectious particles allows the transgene propagation in vitro. Eight days after transfection in vitro, the proportion of cells expressing the transgene is increased by 10-60 times. There was no evidence of replication-competent retrovirus generation in these experiments. The intratumoral injection of this plasmid, but not of the control vector lacking the env gene, led to foci of transgene-expressing cells, suggesting that the transgene had propagated in situ. Altogether, these plasmoviruses combine advantages of viral and non-viral vectors. They should be easy to produce in large quantity as clinical grade materials and should allow efficient and safe in situ targeting of tumor cells.

Keywords: beta-Galactosidase/BIOSYNTHESIS Animal Antiviral Agents/TOXICITY Cell Line Cell Transformation, Neoplastic Comparative Study Deoxycytidine/ANALOGS & DERIVATIVES/METABOLISM DNA Replication/DRUG EFFECTS Ganciclovir/TOXICITY *Gene Therapy Genes, env *Genetic Vectors Male Mice Mice, Inbred BALB C Moloney Leukemia Virus/GENETICS Neoplasms, Experimental/PATHOLOGY Plasmids Proviruses/GENETICS Recombinant Proteins/BIOSYNTHESIS *Retroviridae/GENETICS/PHYSIOLOGY Simplexvirus/ENZYMOLOGY/GENETICS Support, Non-U.S. Gov't Thymidine Kinase/BIOSYNTHESIS *Transfection *Virus Replication 3T3 Cells JOURNAL ARTICLE
960930
M9690889

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