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Methods of diagnosing and treating complications of pregnancy

a technology of hypertension and complications, applied in the field of pregnancy related hypertension disorders, can solve the problems of ineffective monitoring methods, no known cure for pre-eclampsia, and substantial maternal and fetal morbidity and mortality, and achieve the effects of high affinity, and reducing the elevated levels of soluble endoglin

Inactive Publication Date: 2006-03-30
BETH ISRAEL DEACONESS MEDICAL CENT INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012] Using gene expression analysis, we have discovered that levels of soluble endoglin (sE) are markedly elevated in placental tissue samples from pregnant women suffering from pregnancy complications associated with hypertension, including pre-eclampsia. Endoglin is a part of the TGF-β receptor complex that acts to regulate angiogenesis. Endoglin can bind with high affinity to TGF-β family members that are ligands for TGF-β receptors. In affected individuals, excess soluble endoglin may be depleting the placenta of necessary amounts of essential angiogenic and mitogenic factors. I...

Problems solved by technology

Pre-eclampsia is a syndrome of hypertension, edema, and proteinuria that affects 5 to 10% of pregnancies and results in substantial maternal and fetal morbidity and mortality.
However, these monitoring methods are ineffective for diagnosis of the syndrome at an early stage, which could reduce the risk to the subject or developing fetus, if an effective treatment were available.
Currently there are no known cures for pre-eclampsia.

Method used

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  • Methods of diagnosing and treating complications of pregnancy
  • Methods of diagnosing and treating complications of pregnancy
  • Methods of diagnosing and treating complications of pregnancy

Examples

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example 1

Increased Levels of Endoglin mRNA and Protein in Pregnant Women with Pre-Eclampsia

[0247] In an attempt to identify novel secreted factors playing a pathologic role in pre-eclampsia, we performed gene expression profiling of placental tissue from 17 pregnant women with pre-eclampsia and 13 normal pregnant women using Affymetrix U95A microarray chips. We found that the gene for endoglin was upregulated in women with pre-eclampsia.

[0248] In order to confirm the upregulation of endoglin in pre-eclampsia, we performed Northern blots to analyze the placental endoglin mRNA levels (FIG. 3) and western blot analysis to measure serum protein levels of endoglin (FIG. 4) in pre-eclamptic pregnant women as compared with normotensive pregnant women. Pre-eclampsia was defined as (1) a systolic blood pressure (BP)>140 mmHg and a diastolic BP>90 mmHg after 20 weeks gestation, (2) new onset proteinuria (1+by dipstik on urinanalysis, >300 mg of protein in a 24 hour urine collection, or random urine ...

example 2

Demonstration of a Soluble Endoglin Polypeptide in the Placentas and Serum of Pre-Eclamptic Patients

[0250] The western blot analysis used to measure the levels of endoglin protein in placentas and serum from pre-eclamptic women suggested the presence of a smaller protein (63 kDa), that was present in the placenta and serum of pre-eclamptic pregnant women. We have demonstrated that this smaller fragment is the extracellular domain of endoglin. This truncated version is likely to be shed from the placental syncitiotrophoblasts and endothelial cells and circulated in excess quantities in patients with pre-eclampsia. This soluble form of endoglin may be acting as an anti-angiogenic agent by binding to circulating ligands that are necessary for normal vascular health.

example 3

Circulating Concentrations of Soluble Endoglin in Women with Normal Versus Pre-Eclamptic Pregnancies

[0251] In order to compare the levels of circulating, soluble endoglin from the serum of normal, mildly pre-eclamptic, or severely pre-eclamptic women, we performed ELISA analysis on blood samples taken from these women. Patients were divided into mild and severe pre-eclampsia based on the presence or absence of nephritic range proteinuria (>3 g of protein on a 24 hour urine collection or urine protein / creatinine ratio greater than 3.0). The mean urine protein / creatinine ratios in the mild pre-eclampsia group were 0.94±0.2 and in the severe pre-eclampsia group were 7.8±2.1 (FIG. 5). ELISA was performed using a commercially available ELISA kit from R & D Systems, MN (Cat # DNDG00) as previously described (Maynard et al, J. Clin. Invest. 111:649-658, 2003).

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Abstract

Disclosed herein are methods for diagnosing a pregnancy related hypertensive disorder or a predisposition to a pregnancy related hypertensive disorder by measuring the level or biological activity of soluble endoglin. Also disclosed herein are methods for treating a a pregnancy related hypertensive disorder, such as pre-eclampsia and eclampsia, using compounds that alter soluble endoglin levels or biological activity.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of the filing date of U.S. provisional application No. 60 / 613,170, filed Sep. 24, 2004, herein incorporated by reference.STATEMENT AS TO FEDERALLY SPONSORED RESEARCH [0002] This invention was made in part with support from the Government through NIH Grant Nos. DK 064255 and HL 079594. The Government has certain rights in the invention.FIELD OF THE INVENTION [0003] In general, this invention relates to the detection and treatment of subjects having a pregnancy related hypertensive disorder. BACKGROUND OF THE INVENTION [0004] Pre-eclampsia is a syndrome of hypertension, edema, and proteinuria that affects 5 to 10% of pregnancies and results in substantial maternal and fetal morbidity and mortality. Pre-eclampsia accounts for at least 200,000 maternal deaths worldwide per year. The symptoms of pre-eclampsia typically appear after the 20th week of pregnancy and are usually detected by routine measuring of...

Claims

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Application Information

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IPC IPC(8): A61K39/395A61K39/385A61K31/522A61K38/18A61K31/455A61K31/4439A61K31/513
CPCA61K31/4439A61K38/1866A61K31/513A61K31/522A61K38/1841A61K38/1875A61K38/22C07K16/2896G01N33/689G01N2500/00G01N2800/368A61K31/455A61K38/1891Y10T436/143333A61K2300/00A61P15/00A61P43/00A61P9/00A61P9/12A61K39/385A61K38/18A61K39/3955A61K45/06C07K14/495C07K16/2863G01N33/74G01N2333/71G01N2800/60
Inventor KARUMANCHI, S.SUKHATME, VIKAS
Owner BETH ISRAEL DEACONESS MEDICAL CENT INC
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