Methods and pharmaceutical formulations for the treatment of pulmonary hypertension and methods for screening compounds useful in the treatment of pulmonary hypertension

Abstract

A method of treating pulmonary hypertension in a subject in need of such treatment comprises inhibiting EMAP II activity in the subject by an amount effective to treat the pulmonary hypertension in the subject (e.g., in the lungs and more particularly in the pulmonary vasculature). Pharmaceutical formulations useful for carrying out such methods (e.g., an antibody that specifically binds to EMAP II in a pharmaceutically acceptable carrier) and screening techniques useful for identifying additional compounds that can be used for carrying out such methods are also disclosed.

That which is claimed is:  
     
         1 . A method of treating pulmonary hypertension in a subject in need of such treatment, comprising: 
 inhibiting EMAP II activity in the subject by an amount effective to treat pulmonary hypertension in the subject.    
     
     
         2 . The method according to    claim 1   , wherein the inhibiting step is carried out by administering a compound that specifically binds to EMAP II to the subject in an amount effective to treat pulmonary hypertension in the subject.  
     
     
         3 . The method according to    claim 1   , wherein the compound that specifically binds to EMAP II is an antibody.  
     
     
         4 . The method according to    claim 2   , wherein the compound that specifically binds to EMAP II is administered to the subject by inhalation administration.  
     
     
         5 . The method according to    claim 2   , wherein the compound that specifically binds to EMAP II is administered to the subject by intraperitoneal administration.  
     
     
         6 . The method according to    claim 1   , wherein the inhibiting step is carried out by downregulating EMAP II expression in the subject by an amount effective to treat pulmonary hypertension in the subject.  
     
     
         7 . The method according to    claim 6   , wherein downregulating EMAP II expression in the subject is carried out by administering to the subject a compound selected from the group consisting of antisense oligonucleotides that bind to EMAP II mRNA and oligonucleotides that bind to EMAP II DNA.  
     
     
         8 . The method according to    claim 7   , wherein the compound is administered to the subject by inhalation administration.  
     
     
         9 . The method according to    claim 7   , wherein the compound is administered to the subject by intraperitoneal administration.  
     
     
         10 . The method according to    claim 1   , wherein the inhibiting step is carried out by administering an EMAP II receptor antagonist to the subject in an amount effective to treat pulmonary hypertension in the subject.  
     
     
         11 . The method according to    claim 10   , wherein the EMAP II receptor antagonist is administered to the subject by inhalation administration.  
     
     
         12 . The method according to    claim 10   , wherein the EMAP II receptor antagonist is administered to the subject by intraperitoneal administration.  
     
     
         13 . The method according to    claim 1   , wherein the subject is afflicted with primary pulmonary hypertension.  
     
     
         14 . The method according to    claim 1   , wherein the subject is afflicted with secondary pulmonary hypertension.  
     
     
         15 . A method of screening for compounds useful for treating pulmonary hypertension in a subject in need thereof, comprising: 
 contacting a test compound to a probe molecule, the probe molecule selected from the group consisting of EMAP II and fragments thereof; and then    detecting the presence or absence of binding of the test compound to the probe molecule, the presence of binding indicating the compound may be useful for treating pulmonary hypertension in a subject.    
     
     
         16 . The method according to    claim 15   , wherein the test compound is a member of a combinatorial library.  
     
     
         17 . The method according to    claim 15   , wherein the test compound is a protein or peptide.  
     
     
         18 . A method of screening for compounds useful for treating pulmonary hypertension in a subject, comprising: 
 contacting a test compound to probe molecule, the probe molecule selected from the group consisting of DNA encoding EMAP II, RNA encoding EMAP II, and fragments thereof; and then    detecting the presence or absence of binding of the test compound to the probe molecule, the presence of binding indicating the compound may be useful for treating pulmonary hypertension in a subject.    
     
     
         19 . The method according to    claim 18   , wherein the test compound is a member of a combinatorial library.  
     
     
         20 . The method according to    claim 18   , wherein the test compound is an oligonucleotide.  
     
     
         21 . A method of screening for compounds useful for treating pulmonary hypertension in a subject, comprising: 
 determining in vitro whether a test compound inhibits expression of EMAP II;    the inhibition of expression of EMAP II indicating the compound may be useful for treating pulmonary hypertension in a subject.    
     
     
         22 . The method according to    claim 21   , wherein the determining step is carried out in a cell.  
     
     
         23 . The method according to    claim 21   , wherein the determining step comprises determining whether the compound inhibits transcription of EMAP II.  
     
     
         24 . The method according to    claim 21   , wherein the determining step comprises determining whether the compound inhibits translation of EMAP II.  
     
     
         25 . A pharmaceutical formulation useful for treating pulmonary hypertension comprising: 
 a compound selected from the group consisting of compounds that specifically bind to EMAP II, compounds that inhibit the expression of EMAP II, and EMAP II receptor antagonists; and    a pharmaceutically acceptable carrier.    
     
     
         26 . The pharmaceutical formulation according to    claim 25   , wherein the pharmaceutically acceptable carrier is sterile saline solution.  
     
     
         27 . The pharmaceutical formulation according to    claim 25   , wherein the active compound is an antibody that specifically binds to EMAP II.  
     
     
         28 . The pharmaceutical formulation according to    claim 25   , further comprising a supplemental compound selected from the group consisting of vasodilators, calcium channel blockers, anticoagulants, prostacycline, nitroprusside, hydralazine, nitrous oxide, L-arginine, and digoxin.  
     
     
         29 . The pharmaceutical formulation according to    claim 28   , wherein the supplemental compound is a vasodilator selected from the group consisting of adenosine, β-adrenergic agonists, β-adrenergic antagonists, β-adrenergic blockers, α-adrenergic blockers, diuretics, smooth muscle vasodilators, nitrates, and angiotensin-converting enzyme inhibitors.  
     
     
         30 . The pharmaceutical formulation according to    claim 28   , wherein the supplemental compound is a calcium channel blocker selected from the group consisting of nifedipine and diltiazem.