A small molecule that can worm its way past the barrier that separates blood and sperm and snuggle into a crucial pocket needed in the process of making sperm may spell the future for male contraception.
The molecule called JQ1 inhibited the amount and quality of sperm produced by mice in studies led by Dr. Martin M. Matzuk, director of the new Center for Drug Discovery and vice chair of pathology & immunology at Baylor College of Medicine, and Dr. James E. Bradner of Dana-Farber Cancer Institute and Harvard Medical School in Boston, pointing the way toward development of a male contraceptive. The researchers reported in their work in a paper that appears online today in the journal Cell.
"We found that the JQ1 molecule causes a contraceptive effect in males," said Matzuk, also a professor of molecular biology, molecular and human genetics, and pharmacology at BCM. "If you stop the drug, there's complete reversibility."
The research began when Bradner was trying to determine if JQ1 would be valuable as a cancer treatment. He and Matzuk had met earlier when Bradner received a prestigious award from the Burroughs Wellcome Fund. Later Bradner contacted Matzuk about the small molecule. He told Matzuk that he was testing JQ1 as an inhibitor of a member of a family of bromodomain proteins, and he was curious to know whether JQ1 would have an effect on a spermatogenic-specific member of the family called BRDT.
BRDT is involved in the chromatin remodeling process during the generation of sperm in the testis. Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. It is "remodeled" to give the proteins that regulate how genes act access to the genetic material.
Blocks normal process
JQ1 subverts that process by binding to a pocket of BRDT that is necessary for the chromatin remodeling to take place. In doing this, JQ1 blocks the normal process by which sperm are made, thereby reducing production and quality of the sperm.
Matzuk figured how much of the small molecule compound would be required, and Bradner's group sent it to him. Matzuk then starting doing the in vivo experiments in mice himself. Over the next 18 months, he and his group injected mice with JQ1 in solution and evaluated the effect. The mice that received the compound had lower sperm counts and their sperm were less mobile than those of mice who had not received the molecule.
The male mice mated normally, but they were sterile since sperm number and motility of sperm are necessary for fertilization in all mammals including humans.
Using small molecules in this kind of translational research is attractive because they could be put into pill form, in much the same way the female contraceptive is currently packaged. Making proteins for this purpose would be expensive, and they would be difficult to take orally. Also, the small molecule is able to pass easily through the blood-testis barrier, a major obstacle in the past. The blood-testis barrier is a physical barrier between the blood vessels and the seminiferous tubules of the testes (the organs in which sperm originate). The barrier keeps the germ cells out of the bloodstream.
Future drug development
The research points to a new direction in research in male contraceptives, said Matzuk.
"JQ1 is not the pill for men, because it also binds other members of the bromodomain family," he said. "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."
Others who contributed significantly to this research include Michael R. McKeown, Madeleine E. Lemieux and Jun Qi of Dana-Farber; Panagis Filippakopoulos, Sarah Picaud, and Stefan Knapp of the University of Oxford in the UK; Qinglei Li of Texas A&M University in College Station; Lang Ma and Julio E. Agno of BCM; and Richard N. Yu of Children's Hospital Boston.
These studies were supported in part by the Eunice Kennedy Shriver National Institute of Child Health and Human Development as part of the Cooperative Program in Male Contraception, the Alkek Foundation, the Burroughs Wellcome Fund, the National Institutes of Health, the Smith Family Foundation and Damon-Runyon Cancer Research Foundation.
Matzuk holds the Stuart A. Wallace Chair in Pathology & Immunology at BCM and is also Co-Director of the Center for Reproductive Medicine at BCM.