Gene Therapy Fixes Main Cause of Stillbirths and Premature Births in Guinea Pig Model

We owe the lives of billions of people on Earth to a temporary organ that nourished and sustained them in the womb. The placenta, also known as the afterbirth, is considered sacred in some cultures, and its central role in pregnancy was already known at the time of the construction of the Egyptian pyramids. It supplies the fetus with nutrients and oxygen via the umbilical cord, functioning like the intestines, kidneys, liver, and lungs.

New Gene Therapy has Great Potential to Prevent Many Premature Births and Stillbirths

When the placenta fails, there is only one risky option left—inducing labor or performing a cesarean section. Now, the first therapy has been developed that may be able to reverse a condition that is a significant cause of stillbirths and premature births worldwide. It was developed by a team led by a researcher at the University of Florida Health who has been studying this remarkable organ for 20 years. The therapy has proven extremely successful in animal studies. Up to 1 in 10 pregnancies in industrialized countries are affected by placental growth restriction, and twice as many in developing countries. The success of the gene therapy developed by UF Health researcher Helen N. Jones, Ph.D., and a team of colleagues would represent a fundamental change in obstetrics. Optimistically, clinical trials in humans will begin in five years. But Jones, associate professor at the Institute of Physiology and Aging at the UF College of Medicine, said there is good reason for optimism, as in vitro (outside the body) findings from the laboratory show that the treatment could be effective in human tissue.

“This is a very promising therapy,” Jones said. “We are very pleased with our results so far. If all goes well, this could be a game-changer for mothers worldwide. There is the potential to prevent many premature births and give families hope that placental insufficiency does not mean the premature end of a pregnancy.” Placental growth insufficiency, which cuts off the fetus from nutrients and oxygen, leaves doctors and mothers with no way to extend the fetus’s time in the womb. Premature birth can occur many weeks before the due date. “The only thing you can do is deliver the baby and take it to the neonatal intensive care unit,” Jones said. Even if babies survive delivery, often with birth weights well below normal, health problems can arise in later years, including neurological developmental disorders.

The new gene therapy is delivered to the placenta using a polymer nanoparticle so small that about 500 of them would have to be placed side by side to reach the width of a human hair. The nanoparticle carries a payload—a DNA plasmid. This is a piece of harmless DNA that, when introduced into a specific cell type in the placenta, triggers the production of a protein that interacts with the cell and activates chemical processes that can alter or improve cell function. In a sense, the cell receives additional instructions to produce more of this protein. This is crucial because these placentas do not produce enough of it, which leads to their failure.

Treatment Also Lowers the Mother’s Cortisol Levels, Reducing Stress

The cause of placental insufficiency is not yet fully understood. However, scientists have found that these malfunctioning placentas have lower levels of a hormone called insulin-like growth factor 1. Gene therapy stimulates the placenta to produce larger amounts of this growth factor. This hormone stimulates cell growth and development, promotes tissue repair, and ensures that the fetus is supplied with nutrients. Without this hormone, the fetus does not receive enough nutrients to develop and grow properly. What makes insulin-like growth factor 1 particularly interesting to Jones’ team is that it stimulates vascularization, or the formation of blood vessels, which is essential for healthy tissue. In the placenta, this means better nutrient transfer.

“One of the problems with a growth-impaired placenta is that it doesn’t have as good a vascular system as a normal placenta,” Jones said. Jones is the lead author of a study published in Nature Gene Therapy, which she says contains exciting findings. It shows that the therapy promoted placental function and the birth of normal-weight offspring in guinea pigs. Guinea pigs have similar biological and physiological conditions to humans during pregnancy. Surprisingly, the treatment also lowered the mother’s cortisol levels, the stress hormone. If this is also the case in humans, the therapy could help reduce a burden that many mothers know only too well. Stress, according to Jones, is a normal part of pregnancy. However, too much stress can lead to complications that are thought to contribute to high blood pressure, fetal brain development disorders, sleep deprivation, and mental health issues such as depression and anxiety.

Stress can cause problems for both mother and child even years later, including cardiovascular disease and diabetes. Common remedies for maternal stress are not always practical. “Mothers often have to work until they give birth, and there’s nothing they can do about that,” Jones said. “They can’t just sit down and put their feet up. And although their doctors advise them to exercise more, go outside, and not sit at their desks all day, we know that in reality, this often doesn’t work. Treatment like ours could be life-changing for some pregnancies.”