News | HDAC Inhibitors: A Breakthrough in Nonhormonal Male Contraception
Recent surveys show that most men in the United States are interested in male contraceptive medication, but current options are limited to condoms, which can be unreliable, or invasive vasectomy. Recent attempts to develop drugs that prevent sperm production, maturation, or fertilization have had limited success and often provided incomplete protection or caused serious side effects. Because sperm development is extremely complex, researchers have struggled to find safe and effective points of intervention, creating an urgent need for new male contraceptive methods.
Scientists at the Salk Institute have now identified a new, nonhormonal and reversible way to interrupt sperm production. Published on February 20, 2024, in Proceedings of the National Academy of Sciences (PNAS), the study identified a new protein complex that regulates gene expression during sperm production. Treating male mice with an existing HDAC (histone deacetylase) inhibitor disrupted the complex and prevented fertility without affecting libido.
“Most experimental male contraceptives use a forceful approach to block sperm production, while ours is more subtle,” said Professor Ronald Evans, director of Salk's Gene Expression Laboratory. “That makes it a promising therapeutic approach that we hope will advance to human clinical trials soon.”
Background and Findings
The body produces millions of new sperm each day. To do so, sperm stem cells in the testes continuously replicate until they receive a signal to begin becoming sperm, a process called spermatogenesis. The signal comes from retinoic acid, a vitamin A metabolite. Retinoic acid binds to receptors in cells and initiates a complex genetic program that transforms stem cells into mature sperm.
Salk scientists found that retinoic acid receptors must bind to a protein called SMRT, the silencing mediator of retinoic acid and thyroid hormone receptor, for the process to work correctly. SMRT then recruits HDAC, forming a protein complex that coordinates gene expression for sperm production.
Earlier research tried to stop sperm production by directly blocking retinoic acid or its receptors. Retinoic acid is essential to several organ systems, however, so blocking it throughout the body causes multiple side effects. This is why many earlier studies and trials failed to produce a viable drug. Evans and colleagues proposed targeting a molecule downstream of retinoic acid for a more specific effect.
A Pharmacologic Breakthrough
The researchers first studied a previously developed line of genetically engineered mice with a mutation in the SMRT protein that prevented it from binding to retinoic acid receptors. Without this interaction, the mice could not produce mature sperm, but their testosterone levels and mating behavior remained normal, indicating that libido was unaffected.
To determine whether this genetic result could be reproduced pharmacologically, the researchers treated normal mice with MS-275, an oral HDAC inhibitor granted FDA breakthrough status. By blocking activity of the SMRT–retinoic acid receptor–HDAC complex, the drug successfully stopped sperm production without obvious side effects.
Another notable finding was that fertility fully returned within 60 days after treatment stopped, and the offspring developed normally. Researchers said that targeting a molecule downstream of retinoic acid was key to reversibility.
“It is entirely about timing,” said Dr. Michael Downes of the Salk Institute. “When we add the drug, stem cells lose synchronization with the pulses of retinoic acid and sperm production stops. Once the drug is withdrawn, the stem cells can resynchronize with those pulses and sperm production restarts.”
The researchers noted that the drug did not damage sperm stem cells or their genomic integrity. During treatment, the cells continued renewing themselves as stem cells; after withdrawal, they regained the ability to differentiate into mature sperm.
Conclusion
“When we discovered SMRT and created this mouse line, we were not trying to develop a male contraceptive. But when we saw that fertility was blocked, we were able to follow the science toward a potential treatment,” said first author Suk-Hyun Hong, a researcher at the Salk Institute.
News | HDAC Inhibitors: A Breakthrough in Nonhormonal Male Contraception
News | HDAC Inhibitors: A Breakthrough in Nonhormonal Male Contraception
Recent surveys show that most men in the United States are interested in male contraceptive medication, but current options are limited to condoms, which can be unreliable, or invasive vasectomy. Recent attempts to develop drugs that prevent sperm production, maturation, or fertilization have had limited success and often provided incomplete protection or caused serious side effects. Because sperm development is extremely complex, researchers have struggled to find safe and effective points of intervention, creating an urgent need for new male contraceptive methods.
Scientists at the Salk Institute have now identified a new, nonhormonal and reversible way to interrupt sperm production. Published on February 20, 2024, in Proceedings of the National Academy of Sciences (PNAS), the study identified a new protein complex that regulates gene expression during sperm production. Treating male mice with an existing HDAC (histone deacetylase) inhibitor disrupted the complex and prevented fertility without affecting libido.
“Most experimental male contraceptives use a forceful approach to block sperm production, while ours is more subtle,” said Professor Ronald Evans, director of Salk's Gene Expression Laboratory. “That makes it a promising therapeutic approach that we hope will advance to human clinical trials soon.”
Background and Findings
The body produces millions of new sperm each day. To do so, sperm stem cells in the testes continuously replicate until they receive a signal to begin becoming sperm, a process called spermatogenesis. The signal comes from retinoic acid, a vitamin A metabolite. Retinoic acid binds to receptors in cells and initiates a complex genetic program that transforms stem cells into mature sperm.
Salk scientists found that retinoic acid receptors must bind to a protein called SMRT, the silencing mediator of retinoic acid and thyroid hormone receptor, for the process to work correctly. SMRT then recruits HDAC, forming a protein complex that coordinates gene expression for sperm production.
Earlier research tried to stop sperm production by directly blocking retinoic acid or its receptors. Retinoic acid is essential to several organ systems, however, so blocking it throughout the body causes multiple side effects. This is why many earlier studies and trials failed to produce a viable drug. Evans and colleagues proposed targeting a molecule downstream of retinoic acid for a more specific effect.
A Pharmacologic Breakthrough
The researchers first studied a previously developed line of genetically engineered mice with a mutation in the SMRT protein that prevented it from binding to retinoic acid receptors. Without this interaction, the mice could not produce mature sperm, but their testosterone levels and mating behavior remained normal, indicating that libido was unaffected.
To determine whether this genetic result could be reproduced pharmacologically, the researchers treated normal mice with MS-275, an oral HDAC inhibitor granted FDA breakthrough status. By blocking activity of the SMRT–retinoic acid receptor–HDAC complex, the drug successfully stopped sperm production without obvious side effects.
Another notable finding was that fertility fully returned within 60 days after treatment stopped, and the offspring developed normally. Researchers said that targeting a molecule downstream of retinoic acid was key to reversibility.
“It is entirely about timing,” said Dr. Michael Downes of the Salk Institute. “When we add the drug, stem cells lose synchronization with the pulses of retinoic acid and sperm production stops. Once the drug is withdrawn, the stem cells can resynchronize with those pulses and sperm production restarts.”
The researchers noted that the drug did not damage sperm stem cells or their genomic integrity. During treatment, the cells continued renewing themselves as stem cells; after withdrawal, they regained the ability to differentiate into mature sperm.
Conclusion
“When we discovered SMRT and created this mouse line, we were not trying to develop a male contraceptive. But when we saw that fertility was blocked, we were able to follow the science toward a potential treatment,” said first author Suk-Hyun Hong, a researcher at the Salk Institute.
Source:
Collected online