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Iowa Researchers Identify Potential Predictive Marker, Therapeutic Target for Preeclampsia

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NEW YORK (GenomeWeb) – Researchers at the University of Iowa have identified a potential peptide biomarker for preeclampsia.

In a study published last week in Hypertension, the researchers found that plasma vasopressin levels could predict the development of preeclampsia as early as the sixth week of pregnancy. In addition, identification of the marker offers insight into potential therapeutic targets for the disease, Mark Santillan, an assistant professor of maternal fetal medicine at the University of Iowa Carver College of Medicine and first author on the paper, told ProteoMonitor.

A cardiovascular disorder occurring in up to 8 percent of pregnancies, preeclampsia, according to the authors, causes roughly 100,000 maternal deaths per year and is linked to around 25 percent of stillbirths and neonatal deaths in developing countries.

A number of researchers and companies are pursuing predictive and diagnostic tests for the disorder, but effective markers, particularly for early prediction, are still needed.

Santillan and his colleagues decided to look at vasopressin as a potential marker given the fact that the peptide has been linked to hypertension in non-pregnant patients characterized by low circulating renin-angiotensin system activity – a characteristic of preeclamptic women, as well.

Because vasopressin is a challenging molecule to measure – due to its short half-life of between five and 15 minutes – the researchers used a surrogate analyte – copeptin, an inert prosegment of vasopressin that is secreted with it in a one-to-one ratio.

Measuring copeptin levels in a cohort of 54 control pregnant women, 50 pregnant, preeclamptic women, and 33 non-pregnant women, they found that they could predict development of preeclampsia with area under the curve of .90 in the first trimester, .90 in the second trimester, and .78 in the third trimester.

The findings, Santillan said, suggest that vasopressin/copeptin could prove useful "to help triage women with regard to understanding their symptoms," particularly in rural areas or developing countries without easy access to high-risk fetal medicine.

"A lot of the milder symptoms of preeclampsia, like headache and blurry vision and abdominal pain, are things that could be written off in certain cases as kind of normal pregnancy symptoms," he said. "So it's not until you get a [high] blood pressure that you actually might start thinking its preeclampsia."

Were the analyte to hold up in larger cohorts as a useful early prediction marker, clinicians could use it to identify women in need of more frequent blood pressure readings or, perhaps, transfer to high-risk facilities, Santillan said.

Perhaps more interesting, though, he noted, was the insight the study provided into possible therapeutic targets for the disorder. Currently, he said, the only treatment for preeclampsia is delivering the baby, which often means a pre-term delivery, leading to poorer outcomes and higher mortality rates.

Among the challenges to treating the condition has been the fact that researchers aren't entirely clear what conditions underlie it.

"If you get a lot of preeclampsia researchers in a room they will all agree that the core of preeclampsia is a bad placenta that releases a lot of soluble factors, which causes the vascular dysfunction that causes preeclampsia," Santillan said. "But the mechanism by which you get the bad placenta is very varied, and there is a lot of argument as to what is causing what."

The fact that vasopressin was highly elevated as early as six weeks gestation in the preeclamptic pregnancies the Iowa researchers looked at led them to suspect the molecule could be one of the key drivers of the condition.

To test that theory, Santillan and his colleagues developed mouse models of the disease that they infused with vasopressin throughout gestation. These models, he said, matched the phenotypes observed in the human disease as well as any developed to date.

"We're getting pregnancy-specific blood pressure elevation," he said. "We get the proteinuria and kidney problems that we see with the human disease. We also get the OB outcomes – we see not only a smaller litter size but also smaller pups."

These findings suggest that vasopressin-related pathways could prove effective targets for treating the condition, Santillan said, noting that the researchers are now testing the effectiveness of vasopressin antagonists in their mouse models.

The researchers are also investigating whether they can perform the assay in urine, which, he noted, would allow them to package the test in a simple format similar to a pregnancy test, facilitating its use in resource-constrained environments.

"We know that you can measure copeptin in the urine," he said. "And we believe that it will parallel what we are seeing in the plasma, because it is almost all secreted in the urine."

Santillan and his colleagues have filed patents related to both vasopressin's usefulness as a biomarker for the disease and as a therapeutic target and are looking for licensing opportunities.

Licensing the marker to a large company, Santillan said, would allow them to more quickly put together a large cohort for validation of the marker – the next step in the process.

Other outfits developing biomarkers for preeclampsia have in the past similarly cited interest in such a licensing approach. For instance, in a 2012 interview, Katleen Verleysen, CEO of Belgian protein biomarker firm Pronota, which is also developing a preeclampsia test, told ProteoMonitor that such markers could prove a desirable complement to existing preeclampsia offerings from firms including Roche, Abbott, and PerkinElmer, each of which already has tests for the preeclampsia biomarker placenta growth factor, PlGF.

"Every big [in vitro diagnostic] company has an interest in preeclampsia because they all have licenses to PlGF," Verleysen said. "So if we have a test that can identify early on in pregnancy who will be at high risk of developing preeclampsia, that will be very useful to those companies."

Pronota is currently validating its preeclampsia test in a clinical trial using samples collected through the EU-funded Improved Pregnancy Outcomes by Early Detection project.

Maternal and fetal biomarker firm Carmenta Bioscience is also exploring licensing deals for its seven protein preeclampsia panel, CEO Matthew Cooper told ProteoMonitor last year.

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