Inhibiting the cystic fibrosis transmembrane conductance regulator (CFTR) in the cervix as a novel approach to non-hormonal contraception - PROJECT SUMMARY Nonhormonal agents that block the development of highly fluid midcycle cervical mucus would have a contraceptive effect without affecting other aspects of the menstrual cycle. Endocervical cells produce a mucus secretion that varies in viscosity during the menstrual cycle. Under the influence of rising levels of estradiol in natural cycles, mucus changes in consistency from highly viscous and impenetrable to sperm to a highly fluid state that allows sperm to enter and move into the upper genital tract. As progesterone rises with ovulation, mucus consistency rapidly reverts to the viscous impenetrable state. Thick, impenetrable mucus is the mechanism of action of the levonorgestrel IUD, a progestin-only method of contraception that does not block ovulation. “Cervical factor infertility” is the diagnosis for women that have poor mucus quality during otherwise normal ovulatory cycles, and become pregnant with intrauterine insemination that bypasses the cervix. Women with certain mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene develop cervical factor infertility as a manifestation of their cystic fibrosis. CFTR codes for a membrane protein that functions as a chloride/bicarbonate channel, and controls ion and water secretion and absorption in epithelial tissues. Preliminary studies in our lab have documented that CFTR is expressed in endocervical cells, hormonally-regulated, and plays a critical role in the regulation of cervical mucus consistency. Considerable research over the last few decades has led to the discovery of a number of small molecules that act as activators and inhibitors of CFTR. We have identified that the CFTR inhibitor Inh-172 blocks endocervical cell CFTR activity in vitro and in vivo, resulting in an increase in mucus viscosity. In this project, we propose to evaluate the pharmacodynamic (PD) and pharmacokinetic (PK) effects of vaginal administration of Inh-172 in the baboon model. In the R61 phase, we will conduct validation of efficacy studies including mucus physical properties, mucus sperm interactions and in vivo sperm inhibition. During the R33 phase, in collaboration with field-leading vaginal ring drug delivery teams from the Queens University of Belfast, we will formulate Inh-172 into vaginal rings and measure levels of Inh-172 in local vaginal and cervical tissues, compare these to circulating plasma concentrations, and correlate these drug levels with efficacy outcomes. Additionally, we will evaluate safety endpoints including systemic effects of CFTR inhibition as well as local, vaginal health. Results of these experiments will provide proof-of-concept data to support advancement of one or more delivery systems into early phase clinical trials in women.
