Methods And Compositions For The Prevention And Treatment Of Gentiourinary Disorders Including Pre-Term Labor And Leiomyomas

Abstract

The present invention relates to an association between specific polymorphisms of the COMT polypeptide and the development, or risk of developing, preterm labor and uterine diseases and conditions. Disclosed are therapeutic, preventative and diagnostic methods and compositions relating to pre-term labor, uterine diseases and conditions, and ovarian conditions and diseases. In certain embodiments, such methods and compositions involve a COMT inhibitor.

1 . A method of preventing or treating a genitourinary disorder in a patient comprising administering an effective amount of a COMT inhibitor to the patient in need of the inhibitor.  
     
     
         2 . The method of  claim 1 , wherein the genitourinary disorder is selected from the group consisting of: a uterine or ovarian disease or condition, pre-term labor, intrauterine growth restriction, cervical ripping and pre-eclampsia.  
     
     
         3 . (canceled)  
     
     
         4 . The method of  claim 3 , wherein the uterine disease or condition is adenomyosis, endometriosis, endometrial hyperplasia, leiomyosarcoma, benign tumor, malignant tumor, dysfunctional uterine bleeding, endometrial cancer, premenstrual syndrome or abnormal uterine bleeding.  
     
     
         5 . (canceled)  
     
     
         6 . The method of  claim 1 , wherein the ovarian disease or condition is anovulation, irregular ovulation, premature ovulation, or polycystic ovary syndrome.  
     
     
         7 . The method of  claim 1 , wherein the genitourinary disorder concerns pregnancy.  
     
     
         8 . The method of  claim 7 , wherein the genitourinary disorder is pre-term labor, intrauterine growth restriction, cervical ripping or pre-eclampsia.  
     
     
         9 . The method of  claim 1 , further comprising determining a patient is in need of the prevention or treatment.  
     
     
         10 . The method of  claim 9 , wherein determining a patient in need of the prevention or treatment comprises determining whether a patient is at risk for developing a genitourinary disorder or has symptoms of a genitourinary disorder.  
     
     
         11 . (canceled)  
     
     
         12 . The method of  claim 11 , wherein determining whether a patient is at risk for developing a genitourinary disorder comprises identifying the amino acid at position 158 of at least a first COMT polypeptide obtained from the patient.  
     
     
         13 . The method of  claim 4 , wherein the uterine disease or condition is a uterine tumor.  
     
     
         14 .- 15 . (canceled)  
     
     
         16 . The method of  claim 1 , wherein the patient in need of the prevention or treatment has a first allele encoding a valine at position 158 and a second allele encoding a valine at position 158 of a COMT polypeptide.  
     
     
         17 . The method of  claim 1 , wherein the patient in need of the prevention or treatment has a first allele encoding a valine at position 158 and a second allele encoding a methionine at position 158 of a COMT polypeptide.  
     
     
         18 . The method of  claim 1 , wherein the COMT inhibitor is a polypeptide, a nucleic acid or a small molecule.  
     
     
         19 . The method of  claim 1 , wherein the COMT inhibitor decreases the amount of COMT, inhibits the transcription of COMT, inhibits the translation of COMT, inhibits the expression of COMT, or is an antagonist of COMT.  
     
     
         20 .- 23 . (canceled)  
     
     
         24 . The method of  claim 19 , wherein the antagonist is an antibody composition comprising an antibody that recognizes a COMT polypeptide.  
     
     
         25 .- 27 . (canceled)  
     
     
         28 . The method of  claim 1 , wherein the patient was diagnosed or has a genitourinary disorder.  
     
     
         29 . The method of  claim 1 , wherein the patient was previously treated for a genitourinary disorder.  
     
     
         30 . The method of  claim 1 , further comprising administering a second therapy used to treat or prevent a genitourinary disorder.  
     
     
         31 . The method of  claim 30 , wherein the second therapy is selected from the group consisting of radiation therapy, chemotherapy, hormonal therapy, immunotherapy, surgery, gene therapy, hyperthermia, an antibiotic drug, bed rest, a tocolytic drug, a non-estradiol anti-inflammatory drug, and a calcium channel blocker  
     
     
         32 .- 41 . (canceled)  
     
     
         42 . A method of determining whether a patient is at risk for developing a uterine disease or condition or pre-term labor comprising identifying the amino acid at position 158 of at least a first COMT polypeptide obtained from the patient, wherein identifying a valine indicates that the patient is at risk for developing a uterine disease or condition or pre-term labor.  
     
     
         43 . The method of  claim 42 , wherein the uterine disease or condition is adenomyosis, endometriosis, endometrial hyperplasia, leiomyosarcoma, benign tumor, malignant tumor, dysfunctional uterine bleeding, endometrial cancer, premenstrual syndrome or abnormal uterine bleeding.  
     
     
         44 . The method of  claim 42 , further comprising obtaining a sample from the patient.  
     
     
         45 . The method of  claim 42 , wherein the disease or condition is a uterine tumor.  
     
     
         46 .- 47 . (canceled)  
     
     
         48 . The method of  claim 42 , further comprising identifying the amino acid at position 158 of a second COMT polypeptide obtained from the patient, wherein identifying a valine at position 158 of the second COMT polypeptide indicates that the patient is at an increased risk for developing a uterine disease or condition or pre-term labor.  
     
     
         49 . The method of  claim 42 , further comprising identifying the amino acid at position 158 of a second COMT polypeptide obtained from the patient, wherein identifying a methionine at position 158 of the second COMT polypeptide indicates that the patient is at risk for developing a uterine disease or condition or pre-term labor.  
     
     
         50 . The method of  claim 42 , wherein identifying the amino acid at position 158 of the COMT polypeptide comprises determining the nucleic acid sequence of a first COMT gene, wherein the sequencing encodes for the amino acid at position 158 of the COMT polypeptide.  
     
     
         51 . The method of  claim 42 , wherein determining the nucleic acid sequence comprises sequencing the nucleic acid sequence encoding the amino acid at position 158 of the COMT polypeptide.  
     
     
         52 . The method of  claim 42 , wherein identifying the amino acid at position 158 of the COMT polypeptide comprises determining the identity of a nucleic acid sequence in linkage disequilibrium with the nucleic acid sequence encoding an amino acid at position 158 of the COMT polypeptide.  
     
     
         53 . The method of  claim 42 , wherein identifying the amino acid at position 158 of the COMT polypeptide comprises differentiating a nucleic acid sequence encoding a valine from a nucleic acid sequence encoding a methionine at position 158 of the COMT polypeptide obtained from the patient.  
     
     
         54 . The method of  claim 42 , wherein determining whether a patient is at risk for developing a uterine disease or condition further comprises taking a family history or a patient history.  
     
     
         55 . (canceled)  
     
     
         56 . The method of  claim 42 , further comprising treating a patient determined to be at risk for developing a uterine disease or condition.  
     
     
         57 . The method of  claim 56 , wherein the treatment comprises administering an effective amount of a COMT inhibitor to the patient.  
     
     
         58 .- 59 . (canceled)  
     
     
         60 . The method of claim  58 , wherein the hormonal therapy comprises administering a COMT inhibitor to the patient.  
     
     
         61 .- 62 . (canceled)  
     
     
         63 . The method of  claim 42 , wherein the patient is pregnant and exhibits symptoms of pre-term labor.  
     
     
         64 .- 72 . (canceled)  
     
     
         73 . The method of  claim 42 , further comprising treating the patient determined to be at risk for having pre-term labor.  
     
     
         74 . The method of  claim 73 , wherein the treatment comprises administering an effective amount of a COMT inhibitor to the patient.  
     
     
         75 .- 86 . (canceled)  
     
     
         87 . A method of identifying a candidate inhibitor of a uterine disease or condition comprising: 
 (a) providing a COMT polypeptide and a non-methylated catechol-estrogen;    (b) contacting a candidate substance with the COMT polypeptide and the non-methylated catechol-estrogen; and    (c) determining the amount of methylated catechol-estrogen, wherein a decrease in methylated catechol-estrogen, as compared to the amount of methylated catechol-estrogen in the absence of the candidate substance, identifies the candidate substance as a candidate inhibitor of uterine disease or condition.    
     
     
         88 . The method of  claim 87 , further comprising: 
 (d) introducing the candidate inhibitor to a uterine cell; and,    (e) comparing COMT activity in the cell to the COMT activity in a cell not introduced with the candidate inhibitor.    
     
     
         89 . A method of identifying a candidate agent for the prevention or treatment of a genitourinary disorder comprising: 
 (a) contacting a uterine cell expressing a COMT polypeptide with a candidate substance; and    (b) comparing the activity or expression level of COMT polypeptide in the uterine cell contacted with the candidate substance to the activity or expression level of COMT polypeptide in a uterine cell not contacted with the candidate substance, wherein a decrease in activity or expression level in the cell contacted with the candidate substance compared to the cell not contacted with the candidate substance identifies the candidate substance as an agent for the prevention or treatment of a genitourinary disorder.    
     
     
         90 . The method of  claim 89 , wherein the uterine cell is a leiomyoma cell.