“This project for us started very much as a side project,” says Bradner. “We planned together to do a critical first experiment to explore the effects of JQ1 on sperm count and motility. We went right in vivo. And we were shocked at how well the drug worked.”
In one experiment involving about a dozen male mice, the half that had received BRDT daily for three weeks had a sperm count of just over 1 million stored in a part of their epididymis, an order of magnitude lower than their control counterparts, which had 10 million sperm in that same section. The drug also hampered sperm motility and shrank the animals’ testes—a sign, says Bradner, that it was working (though it is not a desirable side effect in humans).
Further tests demonstrated that a high-dose regimen of the drug for several months prevented the male mice from siring pups, though the fertility of the mice rebounded after the drug was removed. “The pups are totally normal,” Bradner says, noting that they performed well on behavioral tests and had normal fertility.
Birth defects remain a “key concern” should the drug move forward toward human trials one day, according to William Bremner, an endocrinologist at the University of Washington in Seattle who was not involved in the current study. But he says that there is good reason to continue studying JQ1 as a potential male contraceptive. “There is reasonable similarity of mice and humans [regarding] spermatogenesis and the blood-testes barrier. Not complete, but close, so mice are reasonable predictors of a human effect.”
But given that people typically use contraceptives for years on end, Mruk would like to see longer studies of the drug to really assess its safety profile. “Short-term side effects can be identified rather quickly,” she says, “but long term side-effects can take decades to fish out.”
Bradner agrees that many follow-up experiments remain to be done. For one, he notes, “it’s unanswered what the role of BRDT is in spermatogenesis”, although it appears to have a key role in the transcription of genes. Bradner has reached out two drug companies, Britain’s GlaxoSmithKline and Tensha Therapeutics of Cambridge, Massachusetts, both of which have worked on inhibitors for the class of proteins to which BRDT belongs. “Both companies expressed some interest,” he says.
The story does not end there for JQ1—just last week researchers from the Boston University School of Medicine found evidence suggesting that it might activate latent HIV in immune cells, and could therefore potentially be useful in eradicating the virus from the body.