Pulmonary hypertension biomarker

Abstract

Pulmonary hypertension is a progressive disease of various origins that is associated with vascular remodelling and results in right heart dysfunction. Accumulating evidence indicates important roles of immune cells and inflammatory chemokines in the pathogenesis and progression of pulmonary hypertension. We have identified CCL21 as anti-remodelling efficacy biomarker for pulmonary hypertension. CCL21 was found to be highly sensitive and specific in discriminating pulmonary hypertension patients from matched controls. CCL21 was upregulated in pulmonary hypertension and down-regulated with treatment with an anti-remodelling agent.

What is claimed is: 
     
         1 . A method for determining if a subject has pulmonary hypertension, comprising
 a) providing a biological sample obtained from a subject suspected of having pulmonary hypertension;   b) assaying the biological sample for the level of CCL21 expression and/or CCL21 protein; and   c) comparing the amount of CCL21 expression and/or of CCL21 protein to a baseline value that is indicative of the amount of CCL21 expression and/or of CCL21 protein in a subject that does not have pulmonary hypertension;   
       wherein a statistical significant increased amount of CCL21 expression and/or of CCL21 protein compared to the baseline value is indicative of pulmonary hypertension. 
     
     
         2 . A method of predicting the likelihood that a patient having pulmonary hypertension will respond to treatment with a pulmonary hypertension antagonist, comprising, assaying a biological sample obtained from the patient for the level of CCL21 expression and/or CCL21 protein; and wherein an increased level of CCL21 expression and/or CCL21 protein relative to a baseline value is indicative of an increased likelihood that the patient will respond to treatment with the pulmonary hypertension antagonist. 
     
     
         3 . A method of treating a patient having pulmonary hypertension, comprising
 a) assaying a biological sample obtained from the patient for the level of CCL21 expression and/or CCL21 protein; and   b) administering a therapeutically effective amount of a pulmonary hypertension antagonist if the patient has a statistical significant increased amount of CCL21 expression and/or CCL21 protein compared to the amount of CCL21 expression and/or of CCL21 protein to a baseline value that is indicative of the amount of CCL21 expression and/or of CCL21 protein in a subject that does not have pulmonary hypertension.   
     
     
         4 . The method according to any one of  claims 1  to  3 , wherein the step of assaying comprises assaying the biological sample for a nucleic acid sequence of CCL21 expression. 
     
     
         5 . The method according to  claim 4 , wherein the nucleic acid is selected from CCL21 ribonucleic acid (RNA) or a fragment thereof and complementary deoxyribonucleic acid (cDNA) or a fragment thereof. 
     
     
         6 . The method according to any one of  claims 1  to  3 , wherein the step of assaying comprises assaying the biological sample for a CCL21 protein or fragment thereof. 
     
     
         7 . The method according to any one of  claims 1  to  6 , wherein the biological sample is selected from blood, serum, plasma, urine, saliva, faeces and a tissue sample. 
     
     
         8 . The method according to any one of  claims 1  to  7 , wherein the step of assaying comprises a technique selected from Northern blot analysis, polymerase chain reaction (PCR), reverse transcription-polymerase chain reaction (RT-PCR), TaqMan-based assays, direct sequencing, dynamic allele-specific hybridization, primer extension assays, oligonucleotide ligase assays, temperature gradient gel electrophoresis (TGGE), denaturing high performance liquid chromatography, high-resolution melting analysis, DNA mismatch-binding protein assays, capillary electrophoresis, Southern Blot, immunoassays, immunohistochemistry, ELISA, flow cytometry, Western blot, HPLC, and mass spectrometry. 
     
     
         9 . A kit for use in determining if a subject has pulmonary hypertension predicting or for use in predicting the likelihood that a patient having pulmonary hypertension will respond to treatment with a pulmonary hypertension antagonist, the kit comprising,
 a) at least one probe capable of detecting the presence of CCL21 expression and/or CCL21 protein; and   b) instruction for using the probe to assay a biological sample from the patient for the presence of CCL21 expression and/or CCL21 protein.   
     
     
         10 . The kit according to  claim 9 , wherein the probe is selected from an oligonucleotide that specifically hybridizes to a region of a nucleic acid sequence of CCL21 expression or binding molecule capable of binding a CCL21 protein or a fragment thereof. 
     
     
         11 . The kit according to  claim 9  wherein the binding molecule is an antibody or a fragment thereof.