Nanoparticle-mediated gene therapy addresses a major cause of stillbirth and premature birth in guinea pig models

Billions of people living on Earth owe their lives to the temporary organs that supported and nourished them in their mothers’ wombs. The placenta, or afterbirth, is considered sacred in some cultures, and its vital role in pregnancy has been recognized as far back as the construction of the Egyptian pyramids. It supplies nutrients and oxygen to the fetus through the umbilical cord and functions like the intestines, kidneys, liver, and lungs.

When the placenta stops working, only one risky option remains. It could be a premature birth due to induced labor or a caesarean section.

Researchers at the University of Florida Health, who have spent two decades studying this remarkable organ, now have the first treatment that could potentially reverse the condition, which is a significant cause of stillbirth and premature birth around the world. Developed by a team led by This treatment has proven to be highly successful in animal studies.

Up to one in 10 pregnancies in developed countries is affected by placental growth restriction, and twice as many in developing countries.

The gene therapy success created by UF Health researcher Dr. Helen N. Jones and her team of collaborators could revolutionize the field of obstetrics.

Optimistically, human clinical trials are five years away.

But Jones, an associate professor in the Department of Physiology and Aging at the University of Florida School of Medicine, said there’s good reason to be optimistic, saying in vitro evidence from the lab shows the treatment is effective in human tissue. He pointed out that this shows that there is a possibility.

“This is a very exciting treatment,” Jones said. “We are very pleased with the results so far. If this works, it could be a game changer for mothers around the world. It could prevent so many preterm births and prevent placental insufficiency from ending early in life. It may give the family hope that there is no ‘pregnancy’ thing. ”

Doctors and mothers have no options for prolonging the fetus’s stay in the uterus because the fetus is deprived of nutrients and oxygen due to placental failure. If your baby is born prematurely, your baby may be born weeks before your expected due date.

“All you can do is deliver the baby and get him to the NICU (neonatal intensive care unit),” Dr. Jones said.

In many cases, babies who are far below normal birth weight are born safely but can develop health problems later in life, including neurodevelopmental disorders.

The new gene therapy is delivered to the placenta by polymer nanoparticles so small that they would need to line up around 500 to be the width of a human hair.

The nanoparticles carry their cargo, a DNA plasmid. This is harmless DNA that, when introduced into certain types of cells in the placenta, triggers the production of proteins that interact with the cells and activate chemical processes that change or enhance cell function.

In a sense, the cell receives additional instructions to produce more of this protein. This is very important because these placentas do not produce enough quantity, leading to failure.

The cause of placental insufficiency is not well understood. But one thing scientists have noticed is that these malfunctioning placentas have low levels of a hormone called insulin-like growth factor 1. Gene therapy induces the placenta to produce larger amounts of growth factors.

This hormone stimulates cell growth and development, promotes tissue repair, and ensures that the fetus is nourished. Without it, the fetus will not receive enough nutrients to develop and grow properly.

What makes insulin-like growth factor 1 particularly appealing to Jones’ team is that it stimulates angiogenesis, or the formation of blood vessels, which is essential for healthy tissue. In the placenta, this improves nutrient transfer.

“One of the characteristics of a growth-restricted placenta is that it doesn’t have as good a vascular tree as a normal placenta,” Jones says.

Jones said he was the senior author of a study published Dec. 4 in the journal Nature Gene Therapy, which details the interesting results. This study shows that in guinea pigs, this therapy improved placental function and promoted the delivery of normal weight pups. Guinea pigs experience biological and physiological conditions similar to humans during pregnancy.

Remarkably, the treatment also reduced the mothers’ levels of the stress hormone cortisol. If this holds true for humans, this therapy could help ease the burden that many mothers know all too well.

Jones says stress is a normal byproduct of pregnancy. However, taking too much can cause complications that are thought to contribute to high blood pressure, inhibiting fetal brain development, lack of sleep, and mental health concerns such as depression and anxiety.

Stress can cause problems such as cardiovascular disease and diabetes for mother and child even years later.

Common treatments for maternal stress are not always practical.

“Moms often have to work right up until the moment they give birth, and there’s nothing we can do to change that,” Jones says. “They just can’t sit and put their legs up. And doctors tell them to exercise more, get outside, and not sit at a desk all day, but in the real world that often doesn’t work. We know that treatments like ours can be life-changing for some pregnancies.”