Methods of diagnosing and treating complications of pregnancy

Abstract

The present invention discloses methods for treating a pregnancy related hypertensive disorder, such as pre-eclampsia and eclampsia, using combinations of compounds that alter soluble endoglin, endothelial nitric oxide synthase, PGI2, TGF-betal, TGF-beta3, activin A, BMP2, BMP7, and sFlt-1 expression levels or biological activity. Also disclosed are methods of diagnosing a pregnancy related hypertensive disorder, such as pre-eclampsia and eclampsia, that include the measurement of any one or more of the following: soluble endoglin, endothelial nitric oxide synthase, PGI2, TGF-betal, TGF-beta3, activin A, BMP2, BMP7, and sFlt-1 expression levels or biological activity.

Description

field of invention

[0001] In general, the present invention relates to the detection and treatment of subjects with pregnancy-related hypertensive disorders. Background of the invention

[0002] Pre-eclampsia is a syndrome of hypertension, edema, and proteinuria that affects 5-10% of pregnancies and results in significant maternal and fetal morbidity and mortality. Preeclampsia is responsible for at least 200,000 maternal deaths per year worldwide. Symptoms of preeclampsia generally appear after the 20th week of pregnancy and are usually detected by routinely measuring a woman's blood pressure and urine. However, these monitoring methods are not effective in diagnosing early syndromes which, if effective treatment is undertaken, would reduce risk to the subject or the developing fetus.

[0003] There are currently no known treatments for preeclampsia. The severity of preeclampsia can range from mild to life-threatening. Mild forms of preeclampsia can be treated with bed ...

Examples

Embodiment 1

[0250] Example 1. Elevated Levels of Endoglin mRNA and Protein in Preeclampsia Pregnant Women

[0251] In an attempt to identify novel secreted factors that play a pathological role in preeclampsia, we performed gene expression profiling of placental tissue from 17 pregnant women with preeclampsia and 13 normal pregnant women using the Affymetrix U95A microarray chip analyze. We found that the gene for endoglin is upregulated in women with preeclampsia.

[0252] To confirm the upregulation of endoglin in preeclampsia, we performed Northern blots to analyze placental endoglin mRNA levels in preeclamptic pregnant women compared with normotensive pregnant women ( image 3 ), and Western blot was performed to measure serum albumin levels of endoglin in preeclamptic pregnant women compared with normotensive pregnant women ( Figure 4 ). Pre-eclampsia was defined as: (1) after 20 weeks of gestation, systolic blood pressure (BP) >140 mmHg and diastolic blood pressure >90 mmHg, (2)...

Embodiment 2

[0254] Example 2. Demonstration of soluble endoglin polypeptide in the placenta and serum of patients with preeclampsia

[0255] Western blot analysis to measure endoglin levels in the placenta and serum of preeclamptic women suggested the presence of a smaller protein (approximately 63-65 kDa) in the placenta and serum of preeclamptic women ( Figure 4 and 30A ). We have shown that this smaller fragment is the extracellular domain of endoglin. This truncated form may be shed from the placental syncytiotrophoblast and endothelial cells and circulates in excess in preeclamptic patients. This soluble form of Endoglin can function as an anti-angiogenic agent by binding circulating ligands essential for normal vascular health.

[0256] The predicted length of the soluble form of the protein is approximately 437 amino acids (including the peptide leader sequence, 412 amino acids without the leader sequence). Purification of sEng from serum of preeclamptic patients. Fractions 4...

Embodiment 3

[0257] Example 3. Circulating Concentrations of Soluble Endoglin in Women with Normal Pregnancies and Preeclampsia

[0258] To compare the levels of circulating soluble endoglin in the serum of normal, mild preeclampsia, or severe preeclampsia women, we performed ELISA analysis on blood samples taken from these women. All patients in this study were recruited at Beth Israel Deaconess Medical Center after obtaining appropriate IRB-approved consent forms. Pre-eclampsia was defined as: (1) after 20 weeks of gestation, systolic blood pressure >140 and diastolic blood pressure >90 in a previously normotensive patient, (2) new-onset proteinuria (1+ , or protein in 24-hour urine collection>300mg, or random urine protein / creatinine ratio>0.3), and (3) by 12 weeks postpartum, hypertension and proteinuria were eliminated. Patients with underlying hypertension, proteinuria, or renal disease were excluded. For the purpose of this study, patients were divided into mild preeclampsia and s...

field of invention

[0001] In general, the present invention relates to the detection and treatment of subjects with pregnancy-related hypertensive disorders. Background of the invention

[0002] Pre-eclampsia is a syndrome of hypertension, edema, and proteinuria that affects 5-10% of pregnancies and results in significant maternal and fetal morbidity and mortality. Preeclampsia is responsible for at least 200,000 maternal deaths per year worldwide. Symptoms of preeclampsia generally appear after the 20th week of pregnancy and are usually detected by routinely measuring a woman's blood pressure and urine. However, these monitoring methods are not effective in diagnosing early syndromes which, if effective treatment is undertaken, would reduce risk to the subject or the developing fetus.

[0003] There are currently no known treatments for preeclampsia. The severity of preeclampsia can range from mild to life-threatening. Mild forms of preeclampsia can be treated with bed ...

Examples

Embodiment 1

[0250] Example 1. Elevated Levels of Endoglin mRNA and Protein in Preeclampsia Pregnant Women

[0251] In an attempt to identify novel secreted factors that play a pathological role in preeclampsia, we performed gene expression profiling of placental tissue from 17 pregnant women with preeclampsia and 13 normal pregnant women using the Affymetrix U95A microarray chip analyze. We found that the gene for endoglin is upregulated in women with preeclampsia.

[0252] To confirm the upregulation of endoglin in preeclampsia, we performed Northern blots to analyze placental endoglin mRNA levels in preeclamptic pregnant women compared with normotensive pregnant women ( image 3 ), and Western blot was performed to measure serum albumin levels of endoglin in preeclamptic pregnant women compared with normotensive pregnant women ( Figure 4 ). Pre-eclampsia was defined as: (1) after 20 weeks of gestation, systolic blood pressure (BP) >140 mmHg and diastolic blood pressure >90 mmHg, (2)...

Embodiment 2

[0254] Example 2. Demonstration of soluble endoglin polypeptide in the placenta and serum of patients with preeclampsia

[0255] Western blot analysis to measure endoglin levels in the placenta and serum of preeclamptic women suggested the presence of a smaller protein (approximately 63-65 kDa) in the placenta and serum of preeclamptic women ( Figure 4 and 30A ). We have shown that this smaller fragment is the extracellular domain of endoglin. This truncated form may be shed from the placental syncytiotrophoblast and endothelial cells and circulates in excess in preeclamptic patients. This soluble form of Endoglin can function as an anti-angiogenic agent by binding circulating ligands essential for normal vascular health.

[0256] The predicted length of the soluble form of the protein is approximately 437 amino acids (including the peptide leader sequence, 412 amino acids without the leader sequence). Purification of sEng from serum of preeclamptic patients. Fractions 4...

Embodiment 3

[0257] Example 3. Circulating Concentrations of Soluble Endoglin in Women with Normal Pregnancies and Preeclampsia

[0258] To compare the levels of circulating soluble endoglin in the serum of normal, mild preeclampsia, or severe preeclampsia women, we performed ELISA analysis on blood samples taken from these women. All patients in this study were recruited at Beth Israel Deaconess Medical Center after obtaining appropriate IRB-approved consent forms. Pre-eclampsia was defined as: (1) after 20 weeks of gestation, systolic blood pressure >140 and diastolic blood pressure >90 in a previously normotensive patient, (2) new-onset proteinuria (1+ , or protein in 24-hour urine collection>300mg, or random urine protein / creatinine ratio>0.3), and (3) by 12 weeks postpartum, hypertension and proteinuria were eliminated. Patients with underlying hypertension, proteinuria, or renal disease were excluded. For the purpose of this study, patients were divided into mild preeclampsia and s...

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