Safety Of Retrovirallentiviral Vectors

The safety of conventional replication-defective retrovirus vectors has been well established over the past decade of clinical trials. However, as retrovirus technology improves and transduction levels in vivo increase, so will the potential for adverse effects. It is already recognized, for example, that the use of human packaging cells

Fig. 9. Suicide gene RCR vectors achieve significant inhibition of intracranial gliomas and persistent expression in migrating tumor foci. Upper panel: Brain section from athymic mouse 5 wk after intracerebral inoculation of U-87 human glioma cells, showing development of multiple tumor foci (numbered) after control treatment with saline (PBS). Primary tumor inoculation site is designated as 1. Middle panel: Brain section from athymic mouse with U-87 glioma after single injection of RCR vector carrying the yeast cytosine deaminase suicide gene (ACE-CD). Immunohistochemical staining with a retrovirus-specific antibody shows vector has spread throughout all visible tumor foci, but does not infect normal brain tissue because of the inability of the retrovirus to infect quiescent cells. Lower panel: Brain section from athymic mouse with U-87 glioma after single injection of ACE-CD vector followed by administration of the specific pro-drug, 5-fluorocytosine (5-FC). This pro-drug is enzymatically converted by yeast cytosine deaminase to the active chemotoxin 5-fluorouracil (5-FU) only in the RCR-transduced glioma cells, resulting in selective killing of the tumor foci.

Fig. 9. Suicide gene RCR vectors achieve significant inhibition of intracranial gliomas and persistent expression in migrating tumor foci. Upper panel: Brain section from athymic mouse 5 wk after intracerebral inoculation of U-87 human glioma cells, showing development of multiple tumor foci (numbered) after control treatment with saline (PBS). Primary tumor inoculation site is designated as 1. Middle panel: Brain section from athymic mouse with U-87 glioma after single injection of RCR vector carrying the yeast cytosine deaminase suicide gene (ACE-CD). Immunohistochemical staining with a retrovirus-specific antibody shows vector has spread throughout all visible tumor foci, but does not infect normal brain tissue because of the inability of the retrovirus to infect quiescent cells. Lower panel: Brain section from athymic mouse with U-87 glioma after single injection of ACE-CD vector followed by administration of the specific pro-drug, 5-fluorocytosine (5-FC). This pro-drug is enzymatically converted by yeast cytosine deaminase to the active chemotoxin 5-fluorouracil (5-FU) only in the RCR-transduced glioma cells, resulting in selective killing of the tumor foci.

will significantly reduce serum inactivation of retrovirus particles, as the presence of ^-galactose epitopes on proteins produced by nonhuman cells is now known to be the primary target of such inactivation by preformed anti-^-galactose antibodies present in human serum, the same antibodies that are responsible for hyperacute rejection in xeno-transplantation (122). Hence retroviral vectors produced in human packaging cells will persist longer in vivo, and so will their attendant risks (123).

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