The administration of an adenoviral thymidine kinase suicide gene to the uterine artery of rabbits does not affect fertility: a safety study of pregnant and nonpregnant rabbits and their offspring

Abstract

Adenoviral gene therapy, based on herpes simplex virus thymidine kinase (AdvTK) is being developed for clinical use but no safety data are available with respect to the effects on female germ cells should the virus accidentally be released into systemic circulation. We studied the effects of AdvTK gene therapy on ovaries and germ cells in pregnant and nonpregnant rabbits and also the potential transmission of a transgene to offspring. To mimic the severest of conditions, gene transfer was made by direct catheter-mediated injection into the uterine artery of pregnant and nonpregnant rabbits. AdvTK or AdvLacZ at 1 x 10(10) pfu were used for gene transfer. Ganciclovir was administered to AdvTK-treated rabbits to induce gene therapy. The rabbits were mated 6 and 12 weeks following gene transfer and the surviving young (89 from a total of 114) were analysed. No change in fertility was observed in the two matings after the gene transfer. In addition, no change was observed in ovarian histology between the AdvTK group, the AdvLacZ group and the nontreated controls. Southern blotting analysis showed no genomic integration of the transgene. However, in PCR analysis, transgene DNA was found in 9.3% of the litter samples. This was not the case for results from the reverse transcription-PCR assay. Although AdvTK gene therapy may initially affect ovarian cells, the influence appears to be transient. However, after direct exposure of the ovarian cells in high concentration of adenoviruses, transmission of a transgene in the offspring cannot be excluded.