Methods of diagnosing and treating complications of pregnancy

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 pregnancy related hypertensive disorder, such as pre-eclampsia and eclampsia, using compounds that alter soluble endoglin levels or biological activity.

1 . A method of treating or preventing a pregnancy related hypertensive disorder in a subject, said method comprising the step of administering to said subject a compound capable of specifically binding to soluble endoglin, wherein said administering is for a time and in an amount sufficient to treat or prevent said pregnancy related hypertensive disorder in said subject. 
     
     
         2 . The method of  claim 1 , wherein said pregnancy related hypertensive disorder is selected from the group consisting of pre-eclampsia, eclampsia, gestational hypertension, chronic hypertension, HELLP syndrome, and pregnancy with a small for gestational age (SGA) infant. 
     
     
         3 . The method of  claim 2 , wherein said pregnancy related hypertensive disorder is pre-eclampsia or eclampsia. 
     
     
         4 . The method  claim 1 , wherein said compound is a purified anti-soluble endoglin antibody or a soluble endoglin antigen-binding fragment. 
     
     
         5 . The method of  claim 1 , wherein said compound is a growth factor. 
     
     
         6 . The method of  claim 5 , wherein said growth factor is selected from the group consisting of: transforming growth factor (TGF)-β1 or TGF-β3, activin A, Bone Morphogenic Protein (BMP)-2 or BMP-7. 
     
     
         7 . The method of  claim 1 , further comprising administering a compound selected from the group consisting of a purified anti-sFlt-1 antibody, an sFlt antigen-binding fragment, nicotine, theophylline, adenosine, nifedipine, minoxidil, magnesium sulfate, vascular endothelial growth factor (VEGF), and placental growth factor (PlGF). 
     
     
         8 . A method of treating or preventing a pregnancy related hypertensive disorder in a subject, said method comprising administering to said subject a compound capable of reducing soluble endoglin expression or biological activity, wherein said administering is sufficient to treat or prevent said pregnancy related hypertensive disorder in said subject. 
     
     
         9 . The method of  claim 8 , wherein said compound is a compound that inhibits a proteolytic enzyme selected from the group consisting of a matrix metalloproteinase (MMP), cathepsin, and elastase. 
     
     
         10 . The method of  claim 8 , wherein said pregnancy related hypertensive disorder is selected from the group consisting of pre-eclampsia, eclampsia, gestational hypertension, chronic hypertension, HELLP syndrome, and pregnancy with a small for gestational age (SGA) infant. 
     
     
         11 . The method of  claim 1 , wherein said method further comprises monitoring said pregnancy related hypertensive disorder in said subject, wherein said monitoring comprises measuring the level of soluble endoglin polypeptide in a sample from said subject. 
     
     
         12 . The method of  claim 11 , wherein the level of soluble endoglin is the level of free, bound, or total soluble endoglin. 
     
     
         13 . The method of  claim 11 , wherein the level of soluble endoglin is the level of an endoglin polypeptide resulting from degradation or enzymatic cleavage. 
     
     
         14 . A method of diagnosing a subject as having, or having a predisposition to, a pregnancy related hypertensive disorder, said method comprising measuring the level of a soluble endoglin polypeptide in a sample from said subject. 
     
     
         15 . The method of  claim 14 , wherein said pregnancy related hypertensive disorder is pre-eclampsia, eclampsia, gestational hypertension, chronic hypertension, HELLP syndrome, and pregnancy with a SGA infant. 
     
     
         16 . The method of  claim 14 , wherein the level of soluble endoglin is the level of free, bound, or total soluble endoglin. 
     
     
         17 . The method of  claim 14 , wherein a level of soluble endoglin greater than 20 ng/ml is a diagnostic indicator of a pregnancy related hypertensive disorder or a predisposition to a pregnancy related hypertensive disorder. 
     
     
         18 . The method of  claim 14 , wherein an increase in the level of said soluble endoglin polypeptide relative to a normal reference is a diagnostic indicator of pregnancy related hypertensive disorder or a predisposition to a pregnancy related hypertensive disorder. 
     
     
         19 . The method of  claim 14 , wherein said measuring of levels is done on two or more occasions and a change in said levels between measurements is a diagnostic indicator of said pregnancy related hypertensive disorder. 
     
     
         20 . The method of  claim 14 , wherein said method further comprises measuring the level of at least one of sFlt-1, VEGF, or PlGF polypeptide in a sample from said subject. 
     
     
         21 . The method of  claim 20 , further comprising calculating the relationship between said levels of soluble endoglin, sFlt-1, VEGF, or PlGF using a metric, wherein an alteration in the relationship between said levels in the subject sample relative to a reference sample, is a diagnostic indicator of a pregnancy related hypertensive disorder in said subject. 
     
     
         22 . The method of  claim 21 , wherein said metric is a soluble endoglin anti-angiogenic index: [(sFlt-1+0.25 soluble endoglin)/PlGF] or [(soluble endoglin+sFlt-1)/PlGF]. 
     
     
         23 . The method of  claim 14 , wherein said sample is a bodily fluid, cell, or tissue of said subject in which said soluble endoglin is normally detectable. 
     
     
         24 . The method of  claim 23 , wherein said bodily fluid is selected from the group consisting of urine, amniotic fluid, blood, serum, plasma, and cerebrospinal fluid. 
     
     
         25 . A method of diagnosing a subject as having, or having a predisposition to, a pregnancy related hypertensive disorder, said method comprising measuring the level of an endoglin nucleic acid molecule in a sample from said subject and comparing it to a reference, wherein an alteration in said levels compared to a reference diagnoses a pregnancy related hypertensive disorder or a predisposition to a pregnancy related hypertensive disorder.