Using chemokine profile (RANTES) as evaluative tool in predicting of pre-term pregnancy complications
Inventors
Mor, Gil G. • Neale, Donna • Romero, Roberto
Assignees
Yale University • US Department of Health and Human Services
Publication Number
US-7790463-B2
Publication Date
2010-09-07
Expiration Date
2026-02-02
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Abstract
The present invention provides methods and compositions related to biomarker profiles for each trimester of pregnancy. The present invention also provides methods for identifying patients at risk of developing a complication of pregnancy, such as preeclampsia. In further embodiments, the present invention relates to methods for the diagnosis of patients with preeclampsia.
Core Innovation
The present invention provides methods and compositions related to biomarker profiles specific to each trimester of pregnancy. It relates to methods for identifying patients at risk of developing pregnancy complications such as preeclampsia, as well as methods for the diagnosis of patients with preeclampsia. The invention involves detecting and assessing levels of one or more biomarkers in blood samples and comparing them to predetermined standards characteristic of normal pregnancy stages, thereby determining or aiding in the determination of risk of preeclampsia.
The background explains that preeclampsia affects up to 8% of pregnancies and is associated with significant perinatal morbidity and mortality. Despite efforts, no definitive etiology or specific predictors have been identified, and the only cure remains delivery of the fetus and removal of the placenta. The hallmark of normal placentation is trophoblast invasion leading to remodeling of spiral arteries, whereas in preeclampsia this process is defective, resulting in diminished blood flow and fetal complications. Early apoptotic changes in trophoblasts appear to initiate preeclampsia, pointing to the need for early identification of patients at risk.
The invention solves the problem of lacking predictors for preeclampsia by providing methods that detect biomarker expression profiles in maternal blood across pregnancy trimesters to identify abnormal changes indicative of increased risk. It includes evaluating trophoblast cell viability and apoptosis in vitro when exposed to serum or plasma from pregnant women. The invention also encompasses kits comprising reagents and trophoblast cells for such assays, and methods to screen candidate compounds regulating biomarker expression for therapeutic purposes.
Claims Coverage
The patent comprises multiple independent claims centered on methods for determining risk of preeclampsia by assessing biomarker expression, involving biomarker profiles, specific biomarkers including RANTES, and classification methods.
Use of RANTES biomarker expression to determine preeclampsia risk
Comparing expression of RANTES in a blood sample from a pregnant woman to a predetermined standard, wherein a significant increase indicates risk of developing preeclampsia.
Use of multiple biomarkers in combination with RANTES
Including additional biomarkers alongside RANTES selected from extensive groups of cytokines, chemokines, growth factors, and apoptotic factors to refine risk determination of preeclampsia.
Trimester-specific predetermined standards for biomarker expression
Comparing biomarker expression to standards specific to the first, second, or third trimester of pregnancy in women not at risk to accurately assess preeclampsia risk respective to pregnancy stage.
Score-based classification method using multiple biomarkers
Comparing expression profiles of two or more biomarkers to predetermined standard profiles using a score-based system to determine risk, including application of machine learning techniques such as support vector machines, k-nearest neighbor classifier, and classification tree analysis.
Detection methods for biomarker expression
Utilizing antibodies or antibody fragments, labeled directly or indirectly, mass spectroscopy, or detecting regulated polypeptides or metabolites associated with the biomarkers to determine expression levels in blood samples.
The claims collectively cover methods for determining risk of preeclampsia based on trimester-specific biomarker expression profiles involving RANTES among other biomarkers, employing statistical and machine learning classification methods, and utilizing various detection reagents and assays. These claims provide a comprehensive framework for early identification of preeclampsia risk using molecular markers.
Stated Advantages
The methods can be used early in pregnancy, including the first trimester, to predict or aid in predicting the likelihood of developing preeclampsia.
The invention enables identification of women at risk before clinical symptoms appear, allowing prospective monitoring and potential intervention.
The methods apply to all trimesters, thus not limited to late pregnancy assessments.
Providing a sensitive assay with reported sensitivity of 81% and specificity of 66% for predicting preeclampsia risk based on reduction in trophoblast viability.
Documented Applications
Methods for determining or aiding in determination that a pregnant woman is at risk of developing preeclampsia by comparing biomarker expression in blood samples to trimester-specific standards.
Methods for diagnosing patients with preeclampsia by assessing biomarker profiles and trophoblast cell viability/apoptosis.
Kits comprising reagents and trophoblast cells to perform assays for risk determination of preeclampsia.
Methods for screening candidate compounds that regulate expression of specific biomarkers to identify potential treatments for preeclampsia.
Methods for screening and validating candidate preeclampsia risk biomarkers through comparing expression levels in populations of pregnant women at risk versus healthy controls.
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