Gene silencing could 'turn off' fertility

Gene silencing could ‘turn off’ fertility

* 20:00 16 October 2007
* news service
* Roxanne Khamsi

A gene-silencing technique that stops sperm binding to eggs might one day translate into an entirely new type of contraceptive, say researchers.

Their preliminary experiments have used a method called RNA interference (RNAi) to block the production of a sperm-binding protein on the surface of egg cells in human and mouse cells.

The approach would avoid the harmful side-effects of hormonal birth control, say researchers. However, they stress that they only have preliminary data and that it will take many years to find out if it will work in humans.

Experts say improvements are needed when it comes to modern-day contraception. Barrier methods such as condoms can reduce physical sensation, while intrauterine devices (IUDs) – small plastic or copper devices placed inside the woman’s uterus – can in rare cases cause infertility. Hormonal birth control pills, meanwhile, have potential side effects that include weight gain, mood swings and, in rare cases, dangerous blood clots.

“Overall there is a need for an entirely new class of contraceptives,” says Zev Williams of Brigham and Women’s Hospital in Boston, Massachusetts, US. “There are really so few options for women today.”
Maturing eggs

To explore this possibility, Williams and his collaborators explored the role of proteins found in the zona pellucida, a membrane surrounding egg cells. Sperm bind to these surface proteins as a first step towards entering and fertilising the egg.

Laboratory experiments conducted by Williams’ collaborators revealed that mice genetically engineered to lack zona pellucida protein 3 (ZP3) were completely infertile. Encouraged by this result, Williams decided to see whether RNA interference could disrupt the production of ZP3 in human cells.

Because of the logistical and ethical problems obtaining human eggs, the researchers focused on a line of cells originally derived from embryonic human kidney in the early 1970s. They engineered the cells to carry active genetic code for ZP3, which is normally only produced by 10 or so maturing eggs in the ovary each month.

The team then exposed the cells to an RNAi treatment that uses short genetic fragments to bind to the messenger RNA responsible for producing ZP3. This creates a double-stranded RNA molecule which the cells see as foreign and destroy with enzymes.
Skin patch

Williams discovered that this RNAi treatment reduced the production of ZP3 protein by 95% in the human cells. By comparison, a control molecule designed to bind to RNA for another protein did not affect ZP3 levels. His team presented the findings at the annual meeting of the American Society for Reproductive Medicine in Washington, DC, US on Tuesday.

Researchers say they hope to test whether RNAi can block pregnancy when given intravenously to normal mice. If future experiments produce promising results the team envisions that RNAi administered through a skin patch or vaginal suppositories could one day work in women.

Williams believes that RNAi will only affect the production of ZP3 in the small number of eggs within the ovary that actively mature each month – not the entire reserve of eggs.…-fertility.html

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