Pre-eclampsia could be treated with mRNA technology

Delivering the baby as early as possible, if possible, is currently the only way to manage the common pregnancy complication of preeclampsia. But now, the disease has been successfully treated in mice by delivering mRNA molecules to the placenta to promote the growth of new blood vessels.

The next step is to test this mRNA therapy in larger animals, such as guinea pigs and non-human primates, said Kelsey Swingle at the University of Pennsylvania. “That’s something we’ve discussed starting in the near future.”

If the therapy proves effective in large animals, the team expects to first test it in people who develop preeclampsia early in pregnancy.

“If you have pre-eclampsia in the eighth or ninth month of pregnancy, you can induce labor early, but if you have severe pre-eclampsia in the fourth or fifth month of pregnancy, early induction is not appropriate. You could lose your child,” the team member said. Michael Mitchellalso at the University of Pennsylvania. “So that’s where treatment can (address) an urgent need.”

It may also be used later in pregnancy to avoid the need to induce labor early, which may affect the health of the baby.

About 1 in 25 women develop preeclampsia during their first pregnancy, which can have serious consequences. Globally, preeclampsia kills an estimated 75,000 women 500,000 babies each year.

Preeclampsia is usually diagnosed based on high blood pressure after 20 weeks of pregnancy and signs of kidney damage, such as protein in the urine. The root cause, Swingle said, is that the arteries that connect the uterus to the placenta fail to develop properly.

So, in theory, promoting the growth of arteries in the placenta could treat preeclampsia. We know that a protein called vascular endothelial growth factor (VEGF) promotes blood vessel growth—the problem is getting it to the placenta.

If proteins like VEGF were simply injected into the bloodstream, they would be cleared quickly, Swingle said. This problem can be overcome by providing a recipe for making proteins in the form of mRNA molecules encapsulated in fatty substances to form lipid nanoparticles (LNPs).

When LNP is taken up by a cell, the mRNA molecule tells the cell how to make the required protein. The molecules break down after a while, so the effects are temporary.

This is how covid-19 mRNA vaccines work, so the approach has been tested in pregnancy, Swingle said. “Many pregnant women have been vaccinated against covid-19.”

The LNPs used in the mRNA covid-19 vaccines are taken up by muscle cells because they are injected directly into them. But if the same LNPs are injected into the blood, they are almost always taken up by liver cells.

So the big challenge for Swingle and her team was to find a way to deliver LNP to the placenta. To achieve this, they created and tested about a hundred LNPs with slightly different chemical properties.

When the team used the most promising LNP to deliver an mRNA molecule encoding VEGF to pregnant mice with preeclampsia, the mice’s blood pressure returned to normal for the remainder of the pregnancy.

“This approach deserves further study in higher order primates and, if animal data demonstrate its safety and efficacy, in women with preeclampsia,” said Peter von Dadelson at King’s College London.

Mouse studies using mRNA encoding fluorescent proteins have shown that LNP is taken up by the spleen and to some extent the liver and the placenta, which is a potential safety issue. Importantly, there was no indication that LNP crossed the mouse placenta and entered the fetus.

While there is currently no treatment for preeclampsia, the risks are particularly great without advanced medical care. “Injectable therapy doesn’t require all of these very expensive and complex standards of care, which could be transformative for applications in developing countries,” Mitchell said.