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Construction and Safety of expression controlled retroviral vectors designed to infect pre-determined recipient cells

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Retroviral vectors are currently the gene delivery vehicles of choice for gene therapy protocols and are usually based upon murine leukaemia virus (MLV) which is able to infect and be expressed in most cell types, as long as they are actively dividing. Usually an ex vivo vector transfer procedure is involved which cannot be applied on a large scale both because of efficiency, safety cost and technical complexity. Further this strategy is not possible for many physically inaccessible, difficult to culture and difficult to infect cells. However, given the present state of vector technology, a general, in-vivo administration of viral vectors would lead to the undesirable delivery of genes to non-target cells, resulting in loss of efficiency as well as safety problems. Thus the improvement of gene transfer techniques especially with regard to the targeting of specific cell types is an absolute pre-requisite for safe, reliable and cheap clinical protocols of the future.
We propose to utilise the expertise of the participating groups in order to construct retroviral vectors that are targeted to predefined cell types, both at the level of gene delivery and of gene expression, and that are able to infect non- or slowly dividing cells. This involves the modification of the viral packaging cell lines with respect to the Env proteins that are produced and the inclusion of genes encoding specific viral proteins that ensure infection of non-dividing cells. It also involves the inclusion of previously defined and tested tissue specific regulatory elements and/or promoters in the vector construct. Finally, basic research work aimed at gaining an understanding of the mechanism controlling the shut-off of retroviral expression in stem cells should allow the construction of non-silenced systems. A combination of these approaches will result in the production of a new generation of retroviral vectors showing controlled delivery and expression in predetermined recipient cells that could be produced on an industrial scale for safe and efficient gene transfer. These systems will be invaluable for facile and inexpensive gene therapy protocols of the future.

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Århus Universitet
EU-Beitrag
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Adresse
130,C.F. Møllers Allé
8000 Århus C
Dänemark

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