Genetic and Small Molecule Advances Bode Well for Male Contraceptive Development
Written by Julio M. Castañeda, Ph.D. and Martin M. Matzuk, M.D., Ph.D., Baylor College of Medicine
The human population—currently, 7.4 billion—has more than doubled in the last 60 years, placing more strain on earth’s limited resources and causing the United Nations and World Health Organization to emphasize the importance of family planning. Sixty years have also passed since the combined hormonal contraceptive pill (the “pill”) for women was approved. Since then, various methods of administering hormones to prevent pregnancy in women have been developed. Shockingly, on the male side, only three viable methods have been developed over several millennia (withdrawal, the condom, and vasectomy). New research in hormonal contraception has led to current clinical trials in men; however, as in women, changes in hormone concentrations have adverse effects in men. Thus, to find a non-hormonal contraceptive for men or women would be a game changer.
Using the mouse as a model, our laboratory has demonstrated that non-hormonal contraception is possible. As described in a recent groundbreaking report, our group collaborated with the Bradner and Knapp laboratories and discovered that the small molecule chemotherapeutic agent, JQ1, inhibits male fertility. JQ1 targets a family of related bromodomain proteins that are greatly expressed in some cancers; one of these proteins is expressed only in the testes. Mice administered JQ1 cease sperm production and sire no offspring; however, all other physiological processes (including sexual activity) remain normal. When the drug was no longer administered, males resumed normal fertility with no effect on the offspring. Currently, our lab is working with researchers at Baylor College of Medicine to optimize JQ1 to make it more specific for the protein expressed only in testes and to bring this optimized small molecule to clinical trials. Indeed, Dr. Matzuk has established the Center for Drug Discovery at Baylor to generate small-molecule libraries to screen potential male contraceptives.
In parallel with the drug discovery efforts in our Center, we recently set up a long-term, international collaboration with the Osaka University laboratory of Dr. Masahito Ikawa, a leading expert on the CRISPR/Cas9 gene editing system used for genome manipulation, to identify genes required for male fertility. Identifying these genes is no small task: nearly 4% of the genome is predominantly expressed in the testis. In collaboration with Dr. Ikawa, our groups screened 54 testis-enriched, evolutionarily conserved genes (present, at least, in mice and humans). Although this screen did not reveal new potential contraceptive targets, these 54 genes can be ruled out as essential for male fertility, saving other laboratories time, money, and wasted effort from research duplication. Our labs are working together to identify other potential targets among the 1,000 genes predominantly expressed in the testis, and their investigations are beginning to pay off. Recently, the Ikawa lab identified a potential target in the calcineurin complex. This protein complex is essential for regulating calcium signaling in cells and can be inhibited by the drugs FK506 and cyclosporin A (both powerful immune suppressants). As with JQ1, these two drugs showed reversible male contraception when administered and withdrawn from male mice. Unfortunately, FK506 and cyclosporin A have several adverse immunosuppressive side effects, which negate their use as viable male contraceptives. However, by working with Baylor’s Center for Drug Discovery, small drug-like molecules that specifically target the sperm calcineurin complex can potentially be identified. We are excited to work toward identifying a wide array of testis-specific targets and to create specific inhibitors of these targets.
The ever-increasing armamentarium of innovative molecular, genetic and bioinformatics technologies and capabilities that continue to evolve will greatly aid and accelerate the identification of new potential male contraceptive targets. Likewise, by mining large libraries of powerful drug-like molecules against these targets, we can tailor male contraceptives to each patient, depending on the characteristics that are most beneficial and satisfactory to them. Using these advancements in technology, the future for non-hormonal male contraception is bright!