One Health Research Leads to Test and Treatment for Preeclampsia

College Station, TX-Many of the health problems in the world today not only impact humans, but also animals and the environment. To find solutions, researchers have increasingly taken a "One Health" approach leading to the development of collaborations as unique as the answers they seek.

One example of this One Health approach involves the work of physicians, veterinarians, and environmental scientists at Texas A&M University (TAMU) and Texas A&M AgriLife Research.  Dr. Jules B. Puschett, a physician and research professor in the Veterinary Pathobiology Department at the College of Veterinary Medicine & Biomedical Sciences (CVM), along with researchers at Texas A&M AgriLife Research, have developed an animal model they hope will lead to a way to predict and prevent preeclampsia in humans.

Preeclampsia, a pregnancy-specific disorder, seen in 3-10 percent of pregnancies, is the second leading cause of maternal and fetal death in the United States.  It is also a leading contributor to the most common cause of maternal and fetal death in developing countries. Presently, there is nothing physicians can do to predict, prevent, or cure this disorder.

Since there is no cure, the most common treatment for this disorder is bed rest until the physician decides whether or not to do a cesarean section.  If the mother and child survive delivery, the mother is at risk for having high blood pressure and diabetes later in life, and the baby has a risk of developing mental abnormalities.

Using a rat model, Puschett's team discovered an elevation in a substance in preeclamptic rats that can be detected in the first few days of pregnancy in urine and blood.  In conjunction with the discovery of this substance, these researchers have also developed a compound that prevents preeclampsia when given to pregnant rats with this elevated substance.  Currently, the team is in the process of collecting more data to receive U.S. Food and Drug Administration (FDA) approval for human clinical trials.

The team found that an elevation of the substance marinobufagenin (MBG) not only indicates, but is a potential cause of the later development of preeclampsia.  A diagnostic test to measure MBG was developed in collaboration with Drs. Luc Berghman and Daad Abi-Ghanem from the TAMU Department of Poultry Science. After this discovery, Puschett and his team, who have been working on this project for six years, measured the blood and urine of human patients and found that MBG was elevated in those patients with a diagnosis of preeclampsia.

"Our intention was not only to measure MBG in the blood, but also in the urine because if we end up trying to screen thousands of patients, it is much easier for the patient to give you a urine specimen than blood," Puschett said.

Their next step was to determine when the level of MBG becomes elevated.  In the preeclamptic rats, elevated levels of MBG were present in the first few days of pregnancy.

"At that time in the pregnancy, the rats didn't yet have high blood pressure or an excess of protein in the urine," Puschett said. "So this is a forecast of the later development of preeclampsia in the rat."

With this discovery, Puschett explained that, potentially, every pregnant woman could be screened for preeclampsia through an examination of MBG levels in urine.  Once the team realized they could predict this illness, they decided they needed to try and prevent it, too.

Puschett approached chemists from the Laboratory for Innovative, Chemistry, and Natural Products-Based Interdisciplinary Drug Discovery (LINCHPIN) at TAMU, Dr. Daniel Romo, a chemistry professor and director of the laboratory; Dr. Jing Li, co-director of the laboratory and Dr. Xinzhong Lai, who previously worked with Romo; and asked them to create a compound that would block MBG's effects, thus preventing preeclampsia.

"The goal of the ongoing collaboration is to broaden the studies of preeclampsia in the Puschett group to investigate all possible predictive agents, which appear in the blood and urine of preeclamptic patients, in order to identify a reliable predictor which can be used to diagnose this disease at its earliest developing stage," Romo said.

The group discovered resibufogenin, or RBG, may be a compound that could be used to prevent the onset of preeclampsia.  Although it differs little from MBG, RBG binds to the MBG substance, preventing MBG's effects.

"Collaborating with Dr. Puschett, we have discovered a potential predictive agent (MBG), as well as an antagonist (RBG) to this agent, which can be used to prevent preeclampsia," Romo said.

To test RBG, the compound was given to rats in early pregnancy.  Puschett said the compound completely prevented preeclampsia, high blood pressure, and abnormal protein levels in the rats' urine.

Currently, the team is in process of gathering enough data and funding to present to the FDA for approval to start providing RBG to human patients.  Puschett said it would probably take two to three years before enough data is collected to present to the FDA.  After the FDA approves the drug, the human clinical trials for RGB will begin for pregnant volunteers who have elevated MBG levels to see if preeclampsia is prevented.

If RBG does not prevent preeclampsia in human patients, Puschett said there are approximately 200 compounds similar to RBG that could be evaluated as antagonists for MBG.  These compounds, he said, could be used to help in an effort to establish a method for "personalized medicine" in preeclampsia.  Personalized medicine is medication and treatment tailored toward the individual needs of the patient.

"We are now planning to broaden these studies to investigate other compounds in this family to identify additional antagonists to these agents, which can potentially prevent and/or treat preeclampsia," Romo said.

Puschett and his team also said they think elevated MBG levels could be a problem in other illnesses such as brain disorders.

For right now, though, the main focus for Puschett and his team is generating enough data to present to the FDA for approval of human trials of RBG.

"First, we are focusing on preeclampsia patients, then we are going to branch out to test the waters in other illnesses," Puschett said.

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