Functional genomics and DEC-Tec to identify germ cell-specific contraceptives

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SUMMARY OF P01 APPLICATION The Strategic Plan 2000 of NICHD states that uncontrolled fertility “is one of the most pressing public health challenges facing the world today,” and in 2014, NICHD identified contraception as one of the three priority areas in implementing its scientific vision. Unintended pregnancies are a major health problem worldwide, and in our country, 45% of pregnancies are unintended, 42% of these end in abortion, and the annual healthcare costs are more than $7 billion. However, there is no oral contraceptive pill for men. Our multidisciplinary groups at Baylor College of Medicine and Osaka University have joined forces for the intellectual, technical, and pharmacologic challenge of defining germ cell-specific pathways essential for fertility and developing high- quality preclinical compounds to target spermatogenesis, sperm maturation, motility, and/or fertilization as effective non-hormonal contraceptives for men and women. Our Program Project Grant application describes a new P01 program based on decades of scientific interactions and discoveries of our investigators. The proposed male fertility-directed and contraceptive-directed studies will use state-of-the-art functional genomics and drug discovery approaches to reach our goals. We propose three projects that focus on testis-specific, epididymis-specific, and/or fertilization-specific targets for which optimal small-molecule ligands have yet to be identified and for which mechanistic data are lacking. The proposal includes an Administrative Core that will oversee the finances and stimulate scientific and translational advances of our team. Central to the projects and our team goals of developing novel contraceptives is our DNA-Encoded Chemistry Technology (DEC-Tec) Core that will 1) screen our candidate contraceptive targets against unique billion-compound libraries, 2) produce lead compounds and probes for in vitro mechanistic studies and in vivo contraceptive testing in mice, and 3) identify preclinical candidates for evaluation in clinical trials in men or women. The major innovative aspects of this P01 proposal are 1) our collective application of CRISPR/Cas9 to expeditiously engineer the mouse genome to interrogate male fertility pathways, and 2) our application of DEC-Tec to economically and rapidly identify high-affinity probes and lead compounds to target our reproductive tract-required proteins for evaluation of function and proof-of-concept contraceptive analysis in vivo. The primary objective of our P01 studies is to have multiple bioavailable, effective, and reversible contraceptives directed at novel reproductive targets for testing in men or women within five years. This novel research program will support an internationally-recognized team of scientists with complementary expertise in organic chemistry, biochemistry, functional genomics, and reproductive biology, and has the potential of a huge healthcare payoff by identifying key male fertility pathways and creating unique contraceptives for reversible disruption of essential spermatogenetic, sperm maturation, and fertilization pathways.