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Content archived on 2024-04-15

PARVOVIRUS BASED LINEAR ANIMAL VECTORS FOR PRODUCTION OF VACCINES AND OTHER USEFUL PROTEINS

Objective

IT IS EXPECTED TO OBTAIN A NEW CLASS OF CLONING VECTORS, WITH INTERESTING PROPERTIES : NOT ONLY THEY ARE NOT ONCOGENIC, BUT THEY MIGHT INHIBIT THE DEVELOPMENT OF SOME TYPES OF TUMORS.
Modification of the genomes of parvoviruses H-1 and MVM, attempting to make them suitable linear vectors, has resulted in:
production of recombinant parvoviruses showing transduction specificity for oncogene-transformed cells and having potential for cancer gene therapy;
programmed cell killing by means of inducible clones of parvoviral genes encoding nonstructural proteins;
demonstration and unravelling of the oncolytic activity of parvoviruses, raising prospects of anticancer applications.

Attempts were made to identify and modify MVM sequences that limit the use of this parvovirus as a vector. An attenuator of virus driven gene expression could be deleted. Since cytotoxic products proved essential for virus replication, a strategy was developed for isolation of cells surviving virus propagation. Oncogenic transformation of a number of human and murine cells enhanced their capacity for expressing MVM and H-1 early genes. The up modulation was especially interesting since these parvoviral nonstructural (NS) proteins were cytotoxic. As a first step towards the construction of an artificial minimchromosome, human deoxyribonucleic acid (DNA) sequences that presumably contain an origin of replication (ori) were isolated, cloned and characterised. However, these sequences no longer functioned as ori after their insertion into circular plasmids, and are now being subcloned in modified parvoviral vectors requiring an exogenous ori for their replication.
THE MOST COMMON GENE VECTOR IS THE CIRCULAR DNA OF BACTERIAL PLASMIDS, WHICH ARE UNABLE TO REPLICATE IN ANIMAL CELLS. GENERALLY, VECTORS FOR ANIMAL CELLS ARE BASED ON ONCOGENIC VIRUSES.

THE PRESENT PROJECT AIMS AT OVERCOMING SUCH LIMITATIONS BY PRODUCING A LINEAR VECTOR CONTAINING PUTATIVE ORIGINS OF MAMMALIAN CELL DNA AND UTILIZING AS FUNCTIONAL TELOMERES THE ENDS OF THE REPLICATIVE FORM OF AUTONOMOUS PARVOVIRUSES.

THESE VIRUSES ARE OF VETERINARY INTEREST, AND VACCINES COULD BE OBTAINED EITHER BY CLONING PARTS OF THEIR GENOME IN E. COLI OR BY MANIPULATING THE VIRUS TO PRODUCE AN APPROPRIATE ANTIGEN IN ANIMAL CELLS. IT IS ALSO PLANNED TO INTRODUCE ANIMAL DNA INTO CONSTRUCTS CONTAINING AT THE TWO ENDS THE TERMINI OF PARVOVIRUS IN ITS REPLICATIVE FORM. ANOTHER INTERESTING PROPERTY OF PARVOVIRUSES IS TO INHIBIT THE DEVELOPMENT OF TUMORS : THE NON PATHOGENIC PARVOVIRAL VECTORS MIGHT BE INTERESTING FOR THIS PURPOSE.

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Coordinator

UNIVERSITE LIBRE DE BRUXELLES
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AV. F.D. ROOSEVELT,50
1050 BRUSSELS
Belgium

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