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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD046228-10
Application #
8437097
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Parrott, Estella C
Project Start
2003-09-24
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
10
Fiscal Year
2013
Total Cost
$271,930
Indirect Cost
$55,451
Name
Meharry Medical College
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
041438185
City
Nashville
State
TN
Country
United States
Zip Code
37208
Katz, Tiffany A; Yang, Qiwei; Treviño, Lindsey S et al. (2016) Endocrine-disrupting chemicals and uterine fibroids. Fertil Steril 106:967-77
Yang, Qiwei; Mas, Aymara; Diamond, Michael P et al. (2016) The Mechanism and Function of Epigenetics in Uterine Leiomyoma Development. Reprod Sci 23:163-75
Abdelaziz, Mohamed; Sherif, Lotfy; ElKhiary, Mostafa et al. (2016) Targeted Adenoviral Vector Demonstrates Enhanced Efficacy for In Vivo Gene Therapy of Uterine Leiomyoma. Reprod Sci 23:464-74
Al-Hendy, Ayman; Diamond, Michael P; Boyer, Thomas G et al. (2016) Vitamin D3 Inhibits Wnt/β-Catenin and mTOR Signaling Pathways in Human Uterine Fibroid Cells. J Clin Endocrinol Metab 101:1542-51
Prusinski, Lauren; Al-Hendy, Ayman; Yang, Qiwei (2016) Developmental exposure to endocrine disrupting chemicals alters the epigenome: Identification of reprogrammed targets. Gynecol Obstet Res 3:1-6
Shalaby, Shahinaz Mahmood; Khater, Mostafa K; Perucho, Aymara Mas et al. (2016) Magnetic nanoparticles as a new approach to improve the efficacy of gene therapy against differentiated human uterine fibroid cells and tumor-initiating stem cells. Fertil Steril 105:1638-1648.e8
Yang, Qiwei; Diamond, Michael P; Al-Hendy, Ayman (2016) The emerging role of extracellular vesicle-derived miRNAs: implication in cancer progression and stem cell related diseases. J Clin Epigenet 2:
Brakta, Soumia; Diamond, Justin S; Al-Hendy, Ayman et al. (2015) Role of vitamin D in uterine fibroid biology. Fertil Steril 104:698-706
Al-Hendy, Ayman; Diamond, Michael P; El-Sohemy, Ahmed et al. (2015) 1,25-dihydroxyvitamin D3 regulates expression of sex steroid receptors in human uterine fibroid cells. J Clin Endocrinol Metab 100:E572-82
Halder, Sunil K; Laknaur, Archana; Miller, Jessica et al. (2015) Novel MED12 gene somatic mutations in women from the Southern United States with symptomatic uterine fibroids. Mol Genet Genomics 290:505-11

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