Male Contraception Research Goes In New Direction

Date: Aug-17-2012A successful test in mice of a molecule that can pass the blood-sperm barrier and render a reversible contraceptive effect in males has taken the quest
for a non-hormonal male contraceptive pill in a new direction, following the results of a new US study reported online in the journal Cell on
Thursday.

The study is significant because it paves the way toward a non-hormonal male contraceptive pill that does not affect sex drive and does not permanently impair
fertility.

The study leaders were Martin M. Matzuk of Baylor College of Medicine (BCM) in Houston, Texas, and James E. Bradner of Dana-Farber Cancer Institute and
Harvard Medical School in Boston.

In their report, the authors describe how a small molecule called JQ1 can cross the barrier that stops sperm entering the bloodstream, find its way into a
pocket that is crucial to the process of making sperm, and disrupt a key protein that makes sperm fertile.

Matzuk, a professor of molecular biology, molecular and human genetics, and pharmacology, told the press:

"We found that the JQ1 molecule causes a contraceptive effect in males."

"If you stop the drug, there's complete reversibility," said Matzuk, who is also director of the new Center for Drug Discovery and vice chair of pathology and
immunology at BCM.
Blocking a Normal Process
JQ1 targets BRDT, a bromodomain protein that plays an important role in making sperm in the testis.

BRDT only exists in the testis and helps control the process of reading the genetic blueprint for making new sperm cells. The process is called chromatin
remodelling and takes place in the nucleus of the sperm cell.

JQ1 binds to a pocket of BRDT which effectively blocks the chromatin remodelling process. The result is fewer sperm of much lower quality.
Experiments in Mice
Once the researchers had figured out what was happening in the test tube, they moved onto testing the effect in mice.

Over 18 months they injected male mice with a solution of JQ1 and measured the result. They found that compared to mice that were not injected with the
molecule, the treated mice had lower sperm counts and their sperm were less mobile (lower motility).

The mice mated normally but they were sterile: their sperm count and motility was below the threshold necessary for fertilization in all mammals, including
humans.
What Next?
There are three things that make this an attractive direction for male contraception research: a small molecule like JQ1 can be made into a pill similar to the
female contraceptive pill; it is a more cost-effective option than using proteins, which are difficult to take by mouth; and the fact it crosses the blood-sperm
barrier, until now a major obstacle in research, also ticks an important box.

However, there is still a lot of work to be done, as Matzuk explains:

"JQ1 is not the pill for men, because it also binds other members of the bromodomain family."

"However, the data is proof of principle that BRDT is an excellent target for male contraception and provides us with useful information for future drug
development," he adds.

A number of organizations funded the study, including the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the Alkek
Foundation, the Fidelity Foundation, the Burroughs Wellcome Fund, the National Institutes of Health, the Smith Family Foundation and Damon-Runyon Cancer
Research Foundation.

Written by Catharine Paddock PhD

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