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Hum. Reprod. Advance Access originally published online on January 8, 2008
Human Reproduction 2008 23(3):514-524; doi:10.1093/humrep/dem410
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© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Toward gene therapy of uterine fibroids: targeting modified adenovirus to human leiomyoma cells

M.H. Hassan1,2, N. Khatoon1, D.T. Curiel3, F.M. Hamada2, H.M. Arafa2 and A. Al-Hendy4,5

1 Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, TX 77555-0587, USA 2 Faculty of Pharmacy, Department of Pharmacology and Toxicology, Al-Azhar University, Cairo, Egypt 3 Gene Therapy Center, University of Alabama at Birmingham, AL 35924, USA 4 Department of Obstetrics and Gynecology, Center for Women's Health Research, Meharry Medical College, 1005 Dr D.B. Todd Jr Blvd., Nashville, TN 37208, USA

5Correspondence address. Tel: +1-615-963-3148; Fax: +1-615-963-3125; E-mail: ahendy{at}mmc.edu

BACKGROUND: To circumvent the paucity of the primary adenovirus (Ad5) receptor and the non-specific Ad5 tropism in the context of uterine leiomyoma cells, Ad5 modification strategies would be beneficial.

METHODS: We screened several modified adenoviruses to identify the most efficient and selective virus toward human leiomyoma cells to be used as candidate for delivering therapeutic genes. We propagated: wild-type Ad5-luc, fiber-modified viruses: ad5 RGD-luc, Ad5-Sigma–luc, Ad5/3-luc and Ad5-CAV2-luc, as well as transcriptional targeted viruses: ad5 survivin-luc, Ad5-heparanase-luc, Ad5-MSLN-CRAD-luc and Ad5-SLPI-luc, on 293 cells and purified them by double CsCL density centrifugation. Then we transfected primary cultures of human leiomyoma cells derived from fibroids of four different patients, telomerase-immortalized human leiomyoma cell line (huLM), telomerase-immortalized normal human myometrial cell line (HM9) and immortalized normal human liver cells (THLE3) with the viruses at 5, 10 and 50 plaque-forming units (PFU)/cell. After 48 h, luciferase activities were measured and normalized to the total cellular protein content.

RESULTS: Ad5-RGD-luc and Ad5-CAV2-luc, Ad5-SLPI-luc and Ad5-MSLN-CRAD-luc at 5, 10 and 50 pfu/cell showed significantly higher expression levels of luciferase activity in both primary and immortalized human leiomyoma cells when compared with Ad5-Luc. Additionally, these modified viruses demonstrated selectivity toward leiomyoma cells, compared with myometrial cells and exhibited lower liver cell transduction, compared with Ad5-luc, at the same dose levels.

CONCLUSIONS: Ad5-CAV2-luc, Ad5-RGD-luc, Ad5-SLPI-luc and Ad5-MSLN-CRAD-luc are promising delivery vehicles in the context of leiomyoma gene therapy.

Key words: uterine leiomyoma/gene therapy/adenovirus targeting strategies

Submitted on June 15, 2007; resubmitted on October 16, 2007; accepted on December 5, 2007.


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