Uterine leiomyoma (fibroids) are the most common gynecologic tumors in premenopausal women and the leading indication for hysterectomy. Uterine fibroids are also a major health disparity issue being 3-4 folds more frequent in African American compared to white women. We have generated most of the literature on the utility of fibroid gene therapy, demonstrating its potential as a localized treatment for uterine leiomyoma that can control the disease while preserving fertility potential. In this proposal we are aiming to screen a wide range of improved adenoviral vector transductional and transcription modifications, to develop an optimal uterine fibroids ON-normal tissue OFF targeted adenoviral vector for effective and safe localized treatment of uterine fibroids. In this revised competing renewal application, we propose three specific aims;
Specific aim one : we will assess adenovirus targeting strategies towards uterine leiomyoma in the Eker rat model. Four targeted adenoviral vectors expressing luciferase gene as a marker (Ad5-RGD-luc, Ad5-CAV2- luc, Ad5-SLPI-luc, and Ad5-MSLN-CRAD-luc) will be directly delivered into the uterine fibroid tumors of the Eker rat, and their efficiency and safety profile will be compared to the parent Ad5-luc first generation unmodified adenoviral vector using bioluminescence imaging and tissue luciferase assays.
Specific aim 2 : we will construct a human leiomyoma-targeted adenovirus vector using best targeting strategy identified above, and then proceed to subclone and express the fibroid therapeutic genes. Three therapeutic genes will be used that we have shown to be effective in local ablation of fibroid lesions;dominant negative estrogen receptor (DN-ER), dominant negative progesterone receptor (DN- PR) or thymidine kinase/ganciclovir (TK/GCV) approach.
Specific aim 3 : In this aim we will test the therapeutic utility of direct intratumor delivery of the three targeted adenoviral vectors (Ad-T-DN-ER, Ad-T-DN-PR and Ad-T-TK) in two animal models;female Eker rats, the only immune competent model for uterine fibroids, and Memy 1, our novel SCID mouse model harboring engrafted human fibroid tissues. The tumors will be sized biweekly by high resolution ultrasound. Functional in vivo PET and SPECT imaging will be used for real time evaluation of tumor proliferation and apoptosis. Detailed evaluation of tumor response as well as additional toxicity and safety assays will be performed. These experiments will provide a valuable model system to further our understanding of the role of estrogen, progesterone and apoptosis in the pathogenesis of uterine fibroids in a unique in vivo setting. This will have major positive effects on minority women health, and reproductive health in general.
For women with symptomatic fibroids who want to preserve fertility, there are currently limited conservative treatment options that will treat their fibroids without compromising subsequent chances of achieving a healthy pregnancy. In this proposal we are aiming to develop an improved gene therapy approach for effective and safe localized treatment of uterine fibroids. Additionally it will enhance our understanding of the role of steroid hormones in pathogenesis of uterine fibroids using unique in vivo model systems.
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