Graphic: how the contraceptive works (print as landscape)

A new kind of contraceptive that does not rely on hormones is being developed, promising women a reliable way of controlling their fertility without side-effects, which can include loss of libido, mood swings and potentially dangerous blood clots.

The fresh approach to contraception will use a revolutionary technique, which won the Nobel Prize for Medicine last year, for switching off genes to disable eggs without affecting future fertility or any other body systems.

Though contraceptives based on the method, known as RNA interference (RNAi), are not expected to be ready for human trials for a decade, they could ultimately transform birth control, offering the first completely new option for half a century.

Because only a woman’s most developed eggs are targeted, the RNAi contraceptive would cause none of the side-effects associated with today’s hormonal Pills. While modern formulations carry fewer risks than older versions, many women find they cause headaches, nausea, weight gain and lowered libido. The Pill also slightly raises the risk of deep-vein thrombosis, heart attacks, strokes and breast cancer.

The new method avoids all these by knocking out a single gene that is essential if eggs are to be fertilised by sperm. RNAi is used to silence the ZP3 gene, which is active only in eggs just before they are ovulated. When ZP3 is switched off, the egg forms without its outer membrane, the zona pellucida. As sperm must bind to the zona pellucida for conception to occur, the result is effective contraception.

The technique will be reversible, as it affects only eggs in the final stages of growth: undeveloped eggs remain untouched, so they can be ovulated normally in the future when women stop taking the drug. As no other cell types express ZP3, there should be no side-effects at all.

Research led by Zev Williams, of Brigham and Women’s Hospital in Boston, Massachusetts, presented yesterday at the American Society for Reproductive Medicine conference in Washington, has shown that mice in which ZP3 has been knocked out are infertile. His team has also established that RNAi can reduce ZP3 activity by more than 90 per cent in both human and animal cell cultures.

More work is still needed to get this closer to 100 per cent, and to find a way of delivering the drug effectively, Dr Williams said. In humans, it is likely to be given via a skin patch or a vaginal suppository, because the molecules on which RNAi relies would not survive stomach acid if taken orally.

These would probably have to be replaced only once a month, making them easier than oral Pills that must be taken every day. Dr Williams hopes to begin animal studies within three to five years, and if these are successful human trials could begin within a decade.

He said there was a “pressing need” for non-hormonal contraceptives, to offer women a reliable method of birth control with no side-effects: “In the 1950s, there were three contraceptive options: hormones, the IUD and barriers. Since then we have had the entire biomolecular revolution in medicine, and yet these three options are still all there is. We simply don’t have a contraceptive drug that is non-hormonal and reversible.

“What we are trying to do is to think about contraception in a new way. Obviously there are going to be big hurdles and it is going to take a lot of time, but the need is there and we think it can be achieved. Using RNAi to target ZP3 is attractive because the gene is active only in growing eggs.

“For women who use hormonal contraceptives to regulate their cycle or to reduce pain, these are likely to remain useful. But for women who use the Pill just as a contraceptive, a non-hormonal approach would be wonderful. You could get all the benefits without the nausea, the headaches, the mood alterations, and the raised risk of thrombosis, stroke and heart attacks.”

British doctors and scientists welcomed the research. Professor Bill Ledger, of the University of Sheffield, said: “I’m always slightly disappointed by what is on offer to women. A lot of them don’t want to rely on a man wearing a condom, and that is very sensible in today’s world. A lot do have side-effects on the Pill and so are anxious about the long-term effects.

“This is a new concept. You are looking at millions of dollars of investment to get it close to the marketplace. If it were available, I am sure a lot of people would want to take it. If it isn’t hormonal, that’s a big selling point.”

Andrew Sharkey, of the University of Cambridge, said: “The oral Pill is nearly 60 years old and there’s been no real advance since then.”

RNAi

— Discovered in 1998 by Craig Mello and Andrew Fire, who won Nobel Prize for Medicine.

— RNA stands for ribonucleic acid, a genetic signalling chemical and cousin of DNA

— Mello and Fire found that short, double-stranded molecules of RNA can switch off genes. RNAi was shown to work in human cells in 2002. It has become a leading field for medical research

Source: Times database

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