No babies, no hormones

RNA may someday replace 'the pill'

SAN FRANCISCO — Poor sperm. After swimming tirelessly to find an egg to fertilize, they may find no place to grab hold, if scientists succeed in creating a new form of hormone-free contraception.

In a new study, researchers infused mouse cells grown in the lab with small, customized RNA molecules. These RNAs prevented the cells from making a protein coating that normally envelops egg cells, the scientists announced June 11 in San Francisco at the Beyond Genome conference.

Sperm must bind to this protein coating before they can enter the egg and fertilize it, so eggs without the coating can’t be fertilized.

“What we’re looking for is an entirely new class of contraceptive,” says lead scientist Zev Williams, a clinical fellow specializing in infertility at Brigham and Women’s Hospital in Boston. Current contraceptive pills “address contraception as a side effect of using hormones,” Williams says. “We would finally start being able to develop a contraceptive that targets fertility itself.”

“It’s extremely novel,” comments Tanuja Koppal, president of New Jersey–based Biomics Consulting and an expert in RNA interference, a process by which the genetic code in short strands of RNA serves as a template for silencing specific genes. “It opens up a whole new arena for fertility drugs.”

Contraception options for women haven’t changed much since hormonal birth control pills became available in the 1960s, Williams notes. For some women, these hormone pills can have unpleasant or dangerous side effects, including irregular bleeding, headaches, blood clots and strokes.

In recent years, scientists have become excited about developing powerful therapies for cancers or viral infections by using RNA interference to mute the activity of key genes underlying those diseases. Williams and his colleagues are the first to consider ways to use RNAi to regulate fertility, Koppal says.

“It seems like a perfect target for RNAi,” Williams says. The thick coating surrounding egg cells consists of three proteins. Williams’ team showed that one of these proteins, ZP3, provides the binding site for sperm. Female mice engineered in previous experiments to lack the gene encoding ZP3 were completely infertile but otherwise healthy. Egg cells from these mice were denuded of the sperm-catching protein coat.

Engineered male mice were unaffected by missing the protein. Only egg cells produce ZP3, and they only do so when the eggs leave the ovaries and wait for sperm to arrive.

Blocking ZP3 production with RNA should be reversible, Williams says, because RNAs in a woman’s body would degrade after one to three months. Women could perhaps apply a vaginal gel containing the RNA molecules once a month or so, Williams suggests. Molecules of RNA would enter blood vessels in the walls of the vagina and then flow in the blood to the uterus and ovaries to reach the egg cells.

Research on RNA-based contraception is still in early stages, Williams notes, and a commercial product is probably 10 years or more away.

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