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Inhibiting the cystic fibrosis transmembrane conductance regulator (CFTR) in the cervix as a novel approach to non-hormonal contraception

Award Number: R61HD114161
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $397,690 )
2025	2025	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	003	2	4/17/2025	NON-COMPETING CONTINUATION	$39,767
2025	2025	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	002	2	2/12/2025	NON-COMPETING CONTINUATION	$0
2025	2025	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	001	2	1/13/2025	NON-COMPETING CONTINUATION	$357,923
2025	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	000	1	1/6/2025	NEW	$0
														Subtotal = $397,690

Issue Date FY: 2024 ( Subtotal = $438,089 )
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Child Health and Human Development Extramural Research	000	1	1/26/2024	NEW	$438,089
														Subtotal = $438,089

Grand Total All Awards = $835,779

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Inhibiting the cystic fibrosis transmembrane conductance regulator (CFTR) in the cervix as a novel approach to non-hormonal contraception

Award Number: R61HD114161

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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