Reversible Non-Hormonal Male Birth Control

Their findings implicate a new protein complex involved in regulating gene expression during sperm production. The researchers demonstrate in mice models the interruption of the function of this protein complex to block fertility without affecting libido using an existing class of drugs called histone deacetylase (HDAC) inhibitors. For this to work the researchers found that retinoic acid receptors must bind with a protein called silencing mediator of retinoid and thyroid hormone receptors (SMRT) which then recruits HDACs, and then the complex of proteins synchronizes the expression of genes that produce sperm.

“Most experimental male birth control drugs use a hammer approach to blocking sperm production, but ours is much more subtle,” says senior author Ronald Evans, professor, director of the Gene Expression Laboratory, and March of Dimes Chair in Molecular and Developmental Biology at Salk. “This makes it a promising therapeutic approach, which we hope to see in development for human clinical trials soon.”

Previous research has tried to stop sperm production by directly blocking retinoic acid or its receptor which can lead to various side effects. This study sought to modulate one of the molecules downstream of retinoic acid to produce a more desirable targeted effect starting in genetically engineered mice in which the SMRT protein was mutated to no longer bind to retinoic acid receptors. 

Without the SMRT-retinoic acid receptor interaction, the mice could not produce mature sperm, but they displayed normal testosterone levels and mounting behavior which indicated that their desire to mate was not affected. To replicate these genetic results with pharmacological interventions unaltered mice were treated with MS-275 which is an oral HDAC inhibitor with FDA breakthrough status. 

Blocking the SMRT-retinoic acid receptor-HDAC complex was found to have successfully stopped sperm production without any obvious side effects, and within 60 days of stopping treatment the animal’s fertility was completely restored with all subsequent offspring developing healthy. According to the researchers, the drug does not damage sperm stem cells or their genomic integrity: when the drug was present, they continued regenerating as stem cells, and when the drug was removed the cells regained the ability to differentiate into mature sperm.

“It’s all about timing,” says co-author Michael Downes, a senior staff scientist in Evans’ lab. “When we add the drug, the stem cells fall out of sync with the pulses of retinoic acid, and sperm production is halted, but as soon as we take the drug away, the stem cells can reestablish their coordination with retinoic acid and sperm production will start up again.”

“We weren’t necessarily looking to develop male contraceptives when we discovered SMRT and generated this mouse line, but when we saw that their fertility was interrupted, we were able to follow the science and discover a potential therapeutic,” says first author Suk-Hyun Hong, a staff researcher in Evans’ lab. “It’s a great example of how Salk’s foundational biological research can lead to major translational impact.”