Researchers from Western and Brown University have made groundbreaking progress towards identifying the root cause and potential therapy for preeclampsia.
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The pregnancy complication affects up to eight percent of pregnancies globally and is the leading cause of maternal and fetal mortality due to premature delivery, complications with the placenta and lack of oxygen.
The research, led by Drs. Kun Ping Lu and Xiao Zhen Zhou at Western, and Drs. Surendra Sharma and Sukanta Jash at Brown, has identified a toxic protein, cis P tau, in the blood and placenta of preeclampsia patients.
According to the study published in Nature Communications, cis P tau is a central circulating driver of preeclampsia—a "troublemaker" that plays a major role in causing the deadly complication.
"The root cause of preeclampsia has (so far) remained unknown, and without a known cause there has been no cure. Preterm delivery is the only life saving measure," said Lu, professor of biochemistry and oncology at Schulich School of Medicine & Dentistry. Lu is also a Western Research Chair in Biotherapeutics.
"Our study identifies cis P tau as a crucial culprit and biomarker for preeclampsia. It can be used for early diagnosis of the complication and is a crucial therapeutic target," said Sharma, professor of pediatrics (research) and professor of pathology and laboratory medicine (research) at Brown.
In 2016, Sharma, a leading preeclampsia researcher, and his team had identified that preeclampsia and diseases like Alzheimer's had similar root causes related to protein issues. This research builds on that finding.
Until now, cis P tau was mainly associated with neurological disorders like Alzheimer's disease, traumatic brain injuries (TBI) and stroke. This association was discovered by Lu and Zhou in 2015 as a result of their decades of research on the role of tau protein in cancer and Alzheimer's.
An antibody developed by Zhou in 2012 to target only the toxic protein while leaving its healthy counterpart unscathed is currently undergoing clinical trials in human patients suffering from TBI and Alzheimer's Disease. The antibody has shown promising results in animal models and human cell cultures in treating the brain conditions.
The researchers were curious whether the same antibody could work as a potential treatment for preeclampsia. Upon testing the antibody in mouse models they found astonishing results.
"In this study, we found the cis P tau antibody efficiently depleted the toxic protein in the blood and placenta, and corrected all features associated with preeclampsia in mice. Clinical features of preeclampsia, like elevated blood pressure, excessive protein in urine and fetal growth restriction, among others, were eliminated and pregnancy was normal," said Sharma, professor of pediatrics (research) and professor of pathology and laboratory medicine (research) at Brown.
Sharma and his team at Brown have been working on developing an assay for early detection of preeclampsia and therapies to treat the condition. He believes the findings of this study have brought them closer to their goal.
"Pin1 plays a pivotal role in keeping proteins, including the tau protein, in the functional shape during stress. When Pin1 becomes inactivated, it leads to the formation of a toxic, misshapen, variant of tau—cis P tau," said Zhou, associate professor, pathology and laboratory medicine at Schulich Medicine and Dentistry.
"Essentially, when Pin1 is activated, it can lead to cancer. On the other hand, when there's a decrease or deactivation in Pin1, it results in the formation of the toxic protein cis P tau, which leads to memory loss in Alzheimer's and after TBI or stroke. Now, we've uncovered its connection to preeclampsia as well," said Zhou. ■