Project 5 seeks to develop adjudin into a non-hormonal contraceptive for men. Adjudin exerts its effects primarily at the Sertoli cell-spermatid interface known as the apical ectoplasmic specialization (apical ES), a testis-specific anchoring junction, without perturbing the hypothalamic-pituitary testicular axis. Specifically, adjudin disrupts actin filament bundles at the Sertoli-spermatid interface, the hallmark ultrastructural feature of the apical ES which is not found in any other anchroing junctions in mammalian tissues, via its intriguing actions on Eps8 (epidermal growth factor receptor pathway substrate 8, an actin bundling protein) and Arp3 (actin-related protein 3, a component ofthe Arp2/3 complex that induces actin filament branching), leading to the conversion of actin filaments at the apical ES from their "bundled" to their "branched" conformation. This, in turn, disrupts spermatid adhesion, inducing spermatid depletion from the epithelium that leads to infertility. Since the population of spermatogonia/spermatogonial stem cells in the seminiferous tubules is not affected, spermatogenesis "re-initiates" in the testis after adjudin is metabolically cleared and fertility rebounds. While adjudin is an effective drug that induces reversible male infertility, subchronic toxicity studies have shown that the margin between its efficacy and safety is narrow. We have now developed an improved formulation of adjudin known as adjudin-IMB which has a 10-fold improvement in its efficacy versus unformulated adjudin, which thus widens the margin between adjudin's efficacy and toxicity, making it a potential drug for male contraceptive development. Studies are proposed to further characterize the efficacy, reversibility, bioavailability, pharmacokinetics and antifertility effects of adjudin-IMB in anticipation of a Phase 1 clinical study in men. Since the molecular targets of adjudin in the testis have recently been identified, we will use cutting-edge technologies to investigate the mechanim(s) by which adjudin perturbs actin filament bundles at the apical ES. We will also examine the mechanism(s) by which adjudin-IMB reaches the apical ES via drug transporters at the blood-testis barrier. Studies outlined in Specific Aims 1 and 2 combined with the proposed subchronic toxicity study (Specific Aim 3) shall prepare us to begin a Phase 1 clinical study in 5 years.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HD029990-22
Application #
8549284
Study Section
Special Emphasis Panel (ZHD1-DRG-H)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
22
Fiscal Year
2013
Total Cost
$170,933
Indirect Cost
Name
Population Council
Department
Type
DUNS #
071050090
City
New York
State
NY
Country
United States
Zip Code
10017
Chen, Haiqi; Mruk, Dolores D; Xia, Weiliang et al. (2016) Effective Delivery of Male Contraceptives Behind the Blood-Testis Barrier (BTB) - Lesson from Adjudin. Curr Med Chem 23:701-13
Tang, Elizabeth I; Mruk, Dolores D; Cheng, C Yan (2016) Regulation of microtubule (MT)-based cytoskeleton in the seminiferous epithelium during spermatogenesis. Semin Cell Dev Biol 59:35-45
Venkatesh, Deepak; Mruk, Dolores; Herter, Jan M et al. (2016) AKAP9, a Regulator of Microtubule Dynamics, Contributes to Blood-Testis Barrier Function. Am J Pathol 186:270-84
Li, Nan; Mruk, Dolores D; Lee, Will M et al. (2016) Is toxicant-induced Sertoli cell injury in vitro a useful model to study molecular mechanisms in spermatogenesis? Semin Cell Dev Biol 59:141-156
Gao, Ying; Lui, Wing-Yee; Lee, Will M et al. (2016) Polarity protein Crumbs homolog-3 (CRB3) regulates ectoplasmic specialization dynamics through its action on F-actin organization in Sertoli cells. Sci Rep 6:28589
Li, Nan; Mruk, Dolores D; Chen, Haiqi et al. (2016) Rescue of perfluorooctanesulfonate (PFOS)-mediated Sertoli cell injury by overexpression of gap junction protein connexin 43. Sci Rep 6:29667
Chen, Haiqi; Mruk, Dolores D; Lee, Will M et al. (2016) Planar Cell Polarity (PCP) Protein Vangl2 Regulates Ectoplasmic Specialization Dynamics via Its Effects on Actin Microfilaments in the Testes of Male Rats. Endocrinology 157:2140-59
Tang, Elizabeth I; Lee, Will M; Cheng, C Yan (2016) Coordination of Actin- and Microtubule-Based Cytoskeletons Supports Transport of Spermatids and Residual Bodies/Phagosomes During Spermatogenesis in the Rat Testis. Endocrinology 157:1644-59
Wen, Qing; Cheng, C Yan; Liu, Yi-Xun (2016) Development, function and fate of fetal Leydig cells. Semin Cell Dev Biol 59:89-98
Jesus, Tito T; Oliveira, Pedro F; Silva, Joaquina et al. (2016) Mammalian target of rapamycin controls glucose consumption and redox balance in human Sertoli cells. Fertil Steril 105:825-833.e3

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