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Simple Paper Test for Point-of-Care Preeclampsia Detection Nearing Commercialization

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NEW YORK (360Dx) – Researchers at The Ohio State University Wexner Medical Center have recently published an evaluation of a paper-based point-of-care assay that purports to accurately detect preeclampsia, a dangerous condition that affects some pregnant women.

The test is now being further developed and commercialized by GestVision, a privately funded company based in Groton, Connecticut.

Preeclampsia is a mysterious disease that afflicts about 10 percent of women who are pregnant or who are in the immediate post-partum period. Its hallmarks include elevated blood pressure and protein in the urine, and it can cause potentially lead to end organ damage to the kidneys or liver. It can also rapidly escalate in severity — a phenomenon captured in the disease's name which stems from the Greek word for lightning — so pregnant woman are monitored for elevated blood pressure and urine proteins beginning in the second trimester.

The disease, which is thought to possibly be caused by improper implantation of the placenta, is associated with increased morbidity and mortality for both mother and baby. Since the only treatment is no longer being pregnant, women suspected of having preeclampsia are often induced into labor before the baby is full term.

However, the symptoms of high blood pressure and protein in the urine can be due to other causes, and the lack of a definitive diagnostic test means that some women with suspected preeclampsia will be induced to deliver their babies pre-term, when this may not actually be required. And, since pre-term delivery itself causes complications, and is extremely costly, an assay that could more definitively tell whether a woman actually has preeclampsia would be beneficial.

The paper-based assay developed at OSU relies on core insights made by husband and wife physician-scientists, Irina and Catalin Buhimschi. The researchers discovered that the protein excreted in the urine of women with preeclampsia is misfolded in such a way that it binds to a dye called Congo Red.

The dye itself has been around since the 1880s and was used in the textile industry before it became a common histology preparation used to stain plants, fungi, and Gram-negative bacteria. Interestingly, it also happens to stain amyloid fibrils that accumulate in certain diseases, such as in amyloid plaques in the brains of patients with Alzheimer's disease.

The Buhimschis' initial insight was originally described in Science Translational Medicine in 2014, and the so-called congophilia of urine from women with preeclampsia has since also been demonstrated in recent studies in Isreal, the UK, and India.

The method was initially developed about eight years ago, while the Buhimschis worked at Yale University — and Yale holds the patents and licenses the technology — and further developed it when they moved to OSU. The two have most recently taken positions at the University of Illinois, but an assay based on the technology they pioneered has been developed into a point-of-care test at OSU.

Developing a simple point-of-care test using Congo Red has taken some perseverance. Kara Rood, a maternal-fetal medicine physician at OSU, was lead author of an E-Clinical Medicine study of the assay published last month and has led the clinical trial there. Although the initial insight was discovered and reported years ago, running the clinical trials and publishing the results have taken time, Rood said.

"We prospectively enrolled women, and their urine was used to perform the Congo Red test. Then we followed them through to see who was diagnosed with preeclampsia and who wasn't," Rood said in an interview.

The test results were blinded to the clinicians, so it was not used for diagnosis but rather to validate that the POC test was "user-friendly and also accurate," Rood said.

As described in the study, this was indeed the case. Of the 346 women enrolled, 217 were admitted for in-patient diagnostic workup for preeclampsia and 112 received a clinical diagnosis of the disease. The Congo Red test, meanwhile, was positive in 86 cases, and adjudication confirmed preeclampsia in 96 cases in all. The Congo Red test was found to have roughly 80 percent sensitivity, 89 percent specificity, 92 percent negative predictive value, and 87 percent accuracy when compared to serum and urine markers.

The test as published consists of a small cardboard folder with a pipette bulb pre-filled with Congo Red dye and filter paper labeled with circles. The user takes an aliquot of a patient's urine with the bulb, shakes to mix it with the dye for 30 seconds, then places drips onto the filter paper.

"If there are no misfolded proteins, the dye stays right where it attaches to the paper, in the middle [of a circle] and the urine spreads out, almost giving a halo around the dye," Rood said. However, in the presence of the misfolded proteins found in women with preeclampsia, the Congo Red dye attaches to the proteins "so when the urine spreads out, it actually carries the dye with it and it makes a much larger circle" on the paper, said Rood, and the spread of the dye is also correlated with severity of symptoms as well.

GestVision has licensed the technology and further developed it to make it more standardized and robust, Rood said. This included manufacturing the test to ensure the accuracy by standardizing the amount of dye, and the standardization of the paper as well as the shelf life of the test, she added.

GestVision is now in the midst of a clinical trial at five US sites in anticipation of submitting the test, called GestAssured, to the US Food and Drug Administration.

Wendy Davis, the CEO of GestVision, said in an email that her firm started working with the Buhimschis in 2012 and took a license to the technology for commercialization in 2014. 

"GestVision designed the test intended for market to be very similar to a pregnancy test," Davis said, noting that is a paper-based lateral flow assay.

Rood will also continue to work on the project, Davis noted, as she is one of the principle investigators for the OSU trial site gathering data for the GestVision FDA submission.