An HDAC inhibitor has been found to stop sperm production and fertility in mice without affecting their libido. Men in the US are interested in using male contraceptives, but current options are limited. Creating effective and safe medications for male contraception has been a challenge due to the complexity of sperm development.
Scientists at the Salk Institute have discovered a new method of interrupting sperm production that is both non-hormonal and reversible. According to a study published in Proceedings of the National Academy of Sciences (PNAS) on February 20, 2024, a new protein complex is involved in regulating gene expression during sperm production. The researchers have demonstrated that treating male mice with HDAC (histone deacetylase) inhibitors, an existing class of drugs, can disrupt the function of this protein complex and prevent fertility without affecting libido.
A Novel Approach
“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.”
The human body produces several million new sperm per day through a process called spermatogenesis. Sperm stem cells continuously make more of themselves until a signal called retinoic acid tells them it’s time to turn into mature sperm. Pulses of retinoic acid bind to retinoic acid receptors which initiates a complex genetic program that turns the stem cells into mature sperm.
Scientists at Salk have discovered that retinoic acid receptors must bind with a protein called SMRT, which recruits HDACs to synchronize the expression of genes that produce sperm. Previous studies have attempted to stop sperm production by blocking retinoic acid or its receptor directly, but this has led to various side effects as retinoic acid is important for multiple organ systems. Evans and his colleagues have instead modulated one of the molecules downstream of retinoic acid to produce a more targeted effect.
The researchers studied a group of genetically engineered mice in which the SMRT protein was mutated and unable to bind to retinoic acid receptors. These mice were not able to produce mature sperm, but their testosterone levels and mating behavior were normal. The researchers then treated normal mice with MS-275, an oral HDAC inhibitor with FDA breakthrough status, which successfully stopped sperm production without producing any noticeable side effects.
The most remarkable aspect of this study is that once the treatment was stopped, the animals’ fertility was completely restored in 60 days, and all subsequent offspring were developmentally healthy. The authors suggest that inhibiting molecules downstream of retinoic acid is key to achieving this reversibility. By removing the HDAC inhibitor, the sperm-producing genes can get back in sync with the pulses of retinoic acid, turning sperm production back on as desired.
“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.”
According to the authors, the drug does not harm the sperm stem cells or their genetic integrity. While the drug is administered, the sperm stem cells maintain their ability to regenerate as stem cells, and when the drug is discontinued, the cells regain their ability to differentiate into mature sperm.
“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.”
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References:
1. “Targeting nuclear receptor corepressors for reversible male contraception” by Suk-Hyun Hong, Glenda Castro, Dan Wang, Russell Nofsinger, Maureen Kane, Alexandra Folias, Annette R. Atkins, Ruth T. Yu, Joseph L. Napoli, Paolo Sassone-Corsi, Dirk G. de Rooij, Christopher Liddle, Michael Downes and Ronald M. Evans, 20 February 2024, Proceedings of the National Academy of Sciences. DOI: 10.1073/pnas.2320129121
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