Bioengineers at the University of Pennsylvania have developed an ionizable lipid nanoparticle formulation containing mRNA for VEGF-A that can be directed to the placenta during pregnancy to dilate blood vessels and treat a serious pregnancy-related complication, preeclampsia.

The findings were published in the article, “Ionizable lipid nanoparticles for in vivo mRNA delivery to the placenta during pregnancy,” in the Journal of the American Chemical Society (JACS) on February 15.  This study in mice, is the first to successfully deliver mRNA to placental cells to treat the root cause of preeclampsia.

The study led by Kelsey Swingle, PhD student in the laboratory of Michael Mitchell, PhD, J. Peter and Geri Skirkanich assistant professor of innovation in bioengineering, reports the development of an ionizable lipid nanoparticle (LNP) that can target and deliver mRNA to trophoblasts, endothelial cells, and immune cells in the placenta.

“Researchers have been doing a lot of work on the mechanisms and movements of drugs into cells, but there is not a lot out there on how therapies can be targeted to treat the root cause of diseases and conditions, particularly during pregnancy,” said Mitchell.

Preeclampsia

Preeclampsia occurs in three to eight percent of pregnancies worldwide, resulting in premature and stillbirths. The hallmark of the disorder is high maternal blood pressure, which results from inadequate dilation of blood vessels in the placenta that in turn restricts blood flow from the mother to the fetus.

At present, preeclampsia can be managed but not treated. A healthcare plan for a pregnant woman with preeclampsia characteristically involves regulated diet, movement, frequent monitoring, blood pressure medications, and frequently, premature delivery. The lack of treatments that target the root cause of preeclampsia, insufficient vasodilation, perpetuates health inequity and poor outcomes in pregnancy related complications.

“Current health care for women with preeclampsia is lacking,” says Swingle. “Many times, the only thing doctors have been able to do is plan for an early delivery, resulting in premature births which come with associated challenges. This approach is only worsening the health of mothers and their babies in places where premature care is limited.”

Lipid nanoparticles

The success of LNPs, as seen in COVID vaccines, is opening doors for new RNA therapies that treat the root causes of disease instead of secondary or tertiary symptoms. Ionizable LNPs constitute the cutting-edge clinical technology for non-viral mRNA delivery.  While ionizable LNPs have been used to carry vaccines and gene editing machinery, their application in treating placental insufficiency during pregnancy has not been investigated until now.

“With no previous research to start from, our first challenge was to figure out which LNPs would travel to and target the placenta,” said Swingle. “We started by creating a library of LNPs using our knowledge from the work we did on LNP delivery to the liver. It turns out the liver and the placenta are very similar. They both receive high blood flow and contain intricate trees of blood vessels.”

Therapy

By pairing a pregnant person’s natural blood flow to the womb with a highly specific ionizable lipid in the LNP, the researchers  targeted and delivered VEGF to placental cells in pregnant mice through a tail vein injection. When placental cells receive VEGF mRNA, they synthesize the protein, which expands blood vessels in the placenta. This reduces maternal blood pressure and restores adequate circulation to the fetus.

“The COVID vaccines were administered as intramuscular injections, a shot in the arm,” said Swingle. “This treatment would be administered intravenously. That means a pregnant woman would be able to be treated via a simple, noninvasive, and pain-free IV drip.”

Health equity

Most drugs in market have not been tested in pregnant women. This creates problems since disorders arising during pregnancy are consequently untreatable before birth.

“I was inspired to research targeted therapies for maternal and fetal health in the spring of 2021 when people were making decisions about getting the COVID vaccine and pregnant women had questions about safety that we could not answer,” said Swingle. “In the case of preeclampsia, many babies are born early, resulting in stunted or abnormal growth and physiological development. A treatment that resolves the issue at the source would allow for higher quality of life and health for both the child and mother over the long term. Addressing this research gap is one way I can be an advocate for women’s health equity.”

Mitchell and his team intend to use their novel LNP platform to develop RNA therapeutics for other pregnancy-related complications.

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