High blood pressure in pregnancy, one of the leading risks to women and babies, could be stopped in its tracks by turning off genes in the placenta. The technique, known as RNA silencing, has worked in a small trial in monkeys, bringing their blood pressure down to normal.
The condition, called pre-eclampsia, affects up to 10 per cent of pregnancies. Affected women can suffer kidney and liver damage, seizures and strokes. When it gets severe the only treatment is to deliver the baby, no matter how early in the pregnancy, so women face choosing between their own health and their baby’s. “It’s very scary,” says Melissa Moore of the University of Massachusetts, who is developing the treatment and has had the condition herself.
Pre-eclampsia occurs when, for some reason, the placenta isn’t effective enough. To compensate, it releases proteins into a woman’s blood to raise her blood pressure, boosting the delivery of nutrients and oxygen to the fetus. But these proteins can push the woman’s blood pressure to dangerously high levels.
Progress in developing treatments has been slow, partly because pharmaceutical firms are nervous about the risk of causing birth defects. A new approach that targets gene activity may be less likely to cause unexpected side-effects because it’s a highly specific treatment. The technique destroys short-strands of DNA-like molecules that are the blueprints for making proteins – called RNA. For pre-eclampsia, it targets the blueprint for one particular placenta protein, called FLT.
A single injection
Moore’s team have tested this approach in a mild version of pre-eclampsia in baboons. They induced pre-eclampsia in nine monkeys, which prompted their placentas to pump out more of the FLT protein. They then injected their RNA therapy into three of the baboons.
Over the following two weeks, the placentas of these three baboons made less FLT, and they showed signs of lower blood pressure and less kidney damage than the six untreated animals.
The offspring of these three monkeys seemed normal, but they were born a little smaller than average. Moore says that could be a result of reducing blood pressure, so they need to do further animal studies to find the optimal therapy dose.
Another RNA therapy for pre-eclampsia that targets a different protein involved in blood pressureis currently being tested in rats. This is being developed by Irish biotech firm Alnylam, which this year brought the first RNA therapy to market, designed against a rare hereditary form of nerve damage.
As well as being highly targeted, RNA therapy is appealing for pre-eclampsia because the treatments do not seem to cross the placenta, making them less likely to affect the fetus. Also, a single injection should be able to target a particular protein for several weeks, making it an appealing treatment in developing countries, where regular medical care may be difficult and pre-eclampsia is a major cause of death in women.
Moore, who is developing RNA therapies for multiple illnesses, has personal reasons for wanting the approach to succeed for this condition. Fifteen years ago, she was scheduled for an emergency Caesarean section with ten weeks of pregnancy still to go, because her blood pressure had been rising dangerously.
While she was being prepped for surgery, a doctor asked her if he could take her placenta for his research into pre-eclampsia. The medic explained that he was part of the team that had just discovered that the FLT protein raises blood pressure in pre-eclampsia.
In the event, Moore’s blood tests temporarily improved and the C-section could be delayed. Her baby was born seven weeks early, but had no lasting ill-effects.
But Moore did make sure her placenta was sent to the researcher, Ananth Karumanchi, of Beth Israel Deaconess Medical Center in Boston. Seven years later, Moore began collaborating with Karumanchi on using her RNA silencing techniques to target the causes of pr-eclampsia. Her own placenta is still in his freezer.
Journal reference: Nature Biotechnology, DOI: 10.1038/nbt.4297