Male Nonhormonal Contraception Via Sphingolipid Biosynthesis Inhibitors

DESCRIPTION (provided by applicant): Contraceptive methods use hormones to prevent germ cell maturation or interfere with sperm-egg fusion via surgery or barriers. Of the ~600 million couples that employ family planning, males are limited to condoms and vasectomies, yet men account for one-third of all contraception. Because of drawbacks to current existing male methods researchers have attempted to develop additional reversible contraceptives for men. The most extensively tested approach utilizes the administration of exogenous testosterone to suppress gonadotropin release thereby depriving the testes of the signals required for spermatogenesis. Drawbacks include the observation that some men fail to respond to hormonal interference and there is a 3-month delay in the onset of azoospermia; therefore, the development of non-hormonal approaches to male contraception is needed. Researchers have noted that male mice inherently devoid of glycosphingolipids (GSL) are sterile but normal in all other aspects. This suggests that inhibitors of GSL biosynthesis may provide a new paradigm for the development of non-hormonal methods of male contraception. Studies have demonstrated that male mice are rendered infertile when treated with miglustat, a sphingolipid mimic, an effect which is fully reversible after discontinuation. This mimic, approved for use in humans for the treatment of Gaucher's disease, inhibits glucosyl transferase, an enzyme responsible for the biosynthetic conversion of ceramide to cerebroside. Sperm from treated mice display abnormal morphologies and lack acrosome antigens but are genetically competent. Unfortunately, for unknown reasons this molecule does not have similar effects in humans or higher species. To better understand the role of glycosphingolipid inhibition in spermatogenesis, we have identified compounds that either inhibit the production or cause the depletion of GSL and will test their in vivo anti-fertility potential. The goal of this project is to explore the ability of glycosphingolipid biosynthesis inhibitors to cause reversible male infertility.