Medicines for Placental Disorders Working Their Way up the Species Ladder

By Deborah Borfitz

January 8, 2025 | The placenta is a temporary but critical organ everyone needs to initiate their life, yet it remains one of the most understudied organs in human biology despite the possible lifelong health implications if anything it is supposed to do goes awry. “Nowadays, it is getting pretty tough to find an adult-onset disease that isn’t related to something that happened during pregnancy,” says Helen Jones, Ph.D., co-director of the Center for Research in Perinatal Outcomes at the University of Florida (UF). 

Conditions tied to placental problems decades earlier include obesity, type 2 diabetes, and cardiovascular complications in both men and women, says Jones, whose research focuses on better understanding the placenta and treating its dysfunctions. Her latest, back-to-back research feats were to demonstrate the safety of a nanoparticle-mediated gene therapy approach to boosting the placenta in normal pregnant macaques (Molecular Human Reproduction, DOI: 10.1093/molehr/gaae038) and another in guinea pigs with fetal growth restriction where the treatment was given multiple times in late pregnancy and found to fully restore fetal weight while reducing both fetal and maternal stress levels (Gene Therapy, DOI: 10.1038/s41434-024-00508-3).   

Jenna Schmidt, Ph.D., co-director of the Precision Medicine and Genomic Resources unit at the Wisconsin National Primate Research Center at the University of Wisconsin–Madison, has been one of Jones’ chief collaborators on this journey. The facility has a decades-long track record of conducting pregnancy studies in rhesus macaques, which share many pregnancy features with humans—notably, trimesters with common development milestones, Schmidt says.  

Jones’ team at UF (primarily Baylea Davenport and Rebecca Wilson, Ph.D.) have several other studies pending publication that look more at the “intricate mechanisms” in the placenta and fetal organs. Next steps include translating the efficacy study done in guinea pigs to macaques to confirm the safety of repeated treatments in late pregnancy, as well as compiling a list of potential targets for the nanoparticle and shifting from its delivery directly into the placenta to an intravenous titration mechanism. 

The “incredibly simple” nanoparticle was developed in the Jones lab specifically for treating fetal growth restriction—a condition that affects between 5% and 8% of pregnancies in the U.S. and 20% or more in some developing countries, she reports. But it could be used for multiple other purposes since it ferries DNA that is used by specific cells depending on the instructions included.  

In the two latest studies, the nanoparticle delivered a DNA code for a human protein called insulin-like 1 growth factor (IGF1), which is important across pregnancy for the development and function of the placenta, Jones says. “We’re basically replacing something that naturally should be there. We know in a lot of growth-restricted human pregnancies the placenta doesn’t make as much of this protein as it should.” 

Treatments “act on the placenta itself, so the protein is locally produced and used,” she adds. “[IGF1] has a role in growth as well as vascular development, so you get a sort of two-for-one impact on the placenta.” 

Early in their studies, the researchers used a “phage screen” to identify some peptides that seemed to preferentially go to the placenta, says Jones. They have since used protein-peptide modeling platforms and artificial intelligence at UF (Hypergator) to identify the placental targets the peptide binds to (Angewandte Chemie, DOI: 10.1002/anie.202405767). 

Translation Possibilities 

When the nanoparticles loaded with the genetic code for IGF1 were injected into the placenta of pregnant macaques in the recent safety study, the DNA strands were successfully taken up and expressed in the animals’ placentas within 24 hours and with no harmful or off-target effects, the investigators report. Moreover, a signal of the transgene’s expression was detected for as long as 10 days after treatment. 

Whether it would likewise hang around in a human placenta for 10 days would have to be tested in clinical trials, the first of which couldn’t start for at least another four years, Jones says. Ultimately, placental gene therapy for fetal growth restriction may need to be administered multiple times or perhaps only once. 

In the efficacy study in guinea pigs, the gene therapy approach showed positive maternal, placental and fetal effects. Together with prior studies in guinea pigs, mice, and human in vitro/ex vivo models, the treatment method looks plausible for future human translation, she says. 

This current track of research is looking at “babies who are born too small and therefore are born too soon because delivery is the only option,” says Jones. “Every day you can keep baby inside of mom really improves the outcomes.” She adds that this is especially important for NICU (neonatal intensive care) survival of very early preterm birth individuals—those born before 32 weeks of pregnancy. 

“What we are aiming to do is restore the growth trajectory across pregnancy,” she continues. “We’re not looking for every [birth] to be an 8-pound bouncing baby; we’re looking for those restricted babies not receiving the right amount of nutrients needed to survive and grow in pregnancy.” 

If they are facing other delivery-related challenges, such as surgery, “it may make all the difference... [to be] just a pound or two heavier at the time of delivery,” says Jones. “We know NICU outcomes improve with every week across pregnancy, and so if we can avoid NICU admittance even by one week that changes the outcomes across the life of that individual.”  

Last year, The Lancet put out a series on preterm birth, small gestational age, and low birthweight under the umbrella of “small vulnerable newborns.” The articles cover the impact in terms of global outcomes and the cost of being born too small and too soon.  

Evidence Gaps

That the placenta has been so understudied reflects the fact that the organ is wrongly associated with women’s health, which broadly suffers from a shortage of interest and funding, Jones says. But whether a fetus is male or female, the placenta supplies everything the developing individual needs. The organ uniquely “juggles communication between two nonidentical individuals... [and] has two blood circulations that, although they do not mix, are very closely apposed, which allows the transfer that happens.”  

Researchers generally move cautiously into the realm of interventional studies on pregnant women due to concerns about unwanted effects on the developing fetus, says Schmidt. So, although their participation in clinical trials is needed to advance prevention and treatment options available to this population, they’re often excluded. 

This was the subject of an exhaustive report by the National Academies of Sciences, Engineering, and Medicine earlier this year, recommending urgent action from congressional and regulating agencies to reverse the longstanding trend. The focus was on overcoming real and perceived liability risks, and the shortage of evidence on the safety and efficacy of drugs during pregnancy.