MEN ARE SNOWFLAKES
On-demand male contraceptive shows promise in preclinical study
An experimental contraceptive drug developed by Weill Cornell Medicine investigators temporarily stops sperm in their tracks and prevents pregnancies in preclinical models. The study, published in Nature Communications on Feb. 14, demonstrates that an on-demand male contraceptive is possible.
The discovery could be a "game-changer" for contraception, according to the study’s co-senior authors Dr. Jochen Buck and Dr. Lonny Levin, who are professors of pharmacology at Weill Cornell Medicine.
Drs. Buck and Levin noted that condoms, which have existed for about 2000 years, and vasectomies have been men's only options to date. Research on male oral contraceptives has stalled, partly because potential contraceptives for men must clear a much higher bar for safety and side effects, Dr. Levin said. Because men don't bear the risks associated with carrying a pregnancy, he explained, the field assumes men will have a low tolerance for potential contraceptive side effects.
Drs. Buck and Levin did not initially set out to find a male contraceptive. They were friends and colleagues with complementary skill sets. But when Dr. Levin challenged Dr. Buck to isolate an important cellular signaling protein called soluble adenylyl cyclase (sAC) that had long eluded biochemists, Dr. Buck couldn't resist. It took him two years. Drs. Buck and Levin then shifted their research focus to studying sAC and eventually merged their laboratories.
The team discovered that mice genetically engineered to lack sAC are infertile. Then in 2018, Dr. Melanie Balbach, a postdoctoral associate in their lab, made an exciting discovery while working on sAC inhibitors as a possible treatment for an eye condition. She found that mice that were given a drug that inactivates sAC produce sperm that cannot propel themselves forward. The team was reassured that sAC inhibition might be a safe contraceptive option by another team’s report that men who lacked the gene encoding sAC were infertile but otherwise healthy.
The new Nature Communications study demonstrate that a single dose of a sAC inhibitor called TDI-11861 immobilizes mice sperm for up to two and half hours and that the effects persist in the female reproductive tract after mating. After three hours, some sperm begin regaining motility; by 24 hours, nearly all sperm have recovered normal movement.
TDI-11861-treated male mice paired with female mice exhibited normal mating behavior but did not impregnate females despite 52 different mating attempts. Male mice treated with an inactive control substance, by contrast, impregnated almost one-third of their mates.
"Our inhibitor works within 30 minutes to an hour," Dr. Balbach said. "Every other experimental hormonal or nonhormonal male contraceptive takes weeks to bring sperm count down or render them unable to fertilize eggs."
Additionally, Dr. Balbach noted that it takes weeks to reverse the effects of other hormonal and nonhormonal male contraceptives in development. She said that since sAC inhibitors wear off within hours, and men would take it only when, and as often, as needed, they could allow men to make day-to-day decisions about their fertility.
Drs. Balbach and Levin noted that it took substantial medicinal chemistry work to develop TDI-11861, and this was accomplished in partnership with the Tri-Institutional Therapeutics Discovery Institute (TDI). The TDI works with investigators from Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center and The Rockefeller University to expedite early-stage drug discovery.
"This highly productive collaboration between TDI and the Buck/Levin lab clearly illustrates the power of partnering pharma-trained drug discovery scientists with academic innovators," said Dr. Peter Meinke, Sanders Director of the TDI.
The Buck/Levin lab’s collaboration with TDI was fostered and nurtured by Weill Cornell Medicine Enterprise Innovation, the office that accelerates the translation and commercialization of technologies arising from research conducted by Weill Cornell faculty and trainees. In addition, Enterprise Innovation is leading the out-licensing of this discovery to their start-up company.
“The team is already working on making sAC inhibitors better suited for use in humans,” Dr. Levin said. Drs. Buck and Levin launched Sacyl Pharmaceuticals with colleague Dr. Gregory Kopf, who serves as the company's Chief Scientific Officer.
The next step for the team is repeating their experiments in a different preclinical model. These experiments would lay the groundwork for human clinical trials that would test the effect of sAC inhibition on sperm motility in healthy human males, Dr. Buck said.
If the drug development and clinical trials are successful, Dr. Levin said he hopes to walk into a pharmacy one day and hear a man request "the male pill."
JOURNAL
Nature Communications
Researchers identify compounds that
could lead to an on-demand, short-term
contraceptive for men
In a mouse study, researchers funded by the National Institutes of Health have identified a potential non-hormonal contraceptive that men could take shortly before sexual activity and have fertility restored the next day. Researchers gave male mice a compound that temporarily disables soluble adenylyl cyclase, the enzyme essential for activating a sperm cell’s ability to swim and mature so that it can travel through the female reproductive tract and fertilize an egg.
In several tests, the researchers showed that the compound TDI-11861 rendered mouse sperm cells immobile and prevented them from maturing. The compounds did not interfere with the animals’ sexual functioning. Although male mice mated with females, no pregnancies were observed. Sperm recovered from female mice remained incapacitated. The authors did not observe any side effects in the male or female mice. The compound wore off three hours later, and males recovered their fertility.
The study was conducted by Melanie Balbach, Ph.D., a postdoctoral fellow in the laboratories of coauthors Jochen Buck, Ph.D., and Lonnie Levin, Ph.D., at Weill Cornell Medical College, New York City, and colleagues. It appears in Nature Communications. Funding was provided by NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute on Aging, and National Cancer Institute.
The researchers say their work provides proof of concept that soluble adenylyl cyclase inhibitors have the potential to provide a safe, on-demand, non-hormonal and reversible oral contraceptive for men.
WHO:
Christopher C. Lindsey, Ph.D., a program official in the NICHD Contraception Research Branch, is available for comment.
ARTICLE:
Balbach, M. Research Letter: On-demand male contraception via acute inhibition of soluble adenylyl cyclase. Nature Communications.2022. https://doi.org/10.1038/s41467-023-36119-6
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About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): NICHD leads research and training to understand human development, improve reproductive health, enhance the lives of children and adolescents, and optimize abilities for all. For more information, visit https://www.nichd.nih.gov.
About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit https://www.nih.gov.
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JOURNAL
Nature Communications
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