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.
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