Treatment of congestive heart failure and other cardiac dysfunction using a gdf15 modulator

Abstract

The invention provides methods and compositions of treating a subject having a cardiac-related disorder such as congestive or chronic heart failure (CHF), cardiac hypertrophy, cardiac hypotrophy, and other cardiac myopathies/dystrophies. The methods comprise administering an effective amount of a composition that modulates, for example, reduces or inhibits, GDF15 activity in the subject.

1 . (canceled) 
     
     
         2 . (canceled) 
     
     
         3 . A method of treating a subject having a cardiac disorder or dysfunction, the method comprising administering an effective amount of a composition comprising a GDF15 modulator thereby to ameliorate a symptom of the cardiac disorder or dysfunction. 
     
     
         4 . The method of  claim 3 , wherein the subject has elevated GDF15 activity in a body fluid. 
     
     
         5 . A method of reducing or reversing cardiac hypotrophy in a subject exhibiting one or more symptoms of congestive heart failure, the method comprising administering an effective amount of a composition comprising a GDF15 modulator, wherein the composition ameliorates at least one symptom of cardiac hypotrophy in the subject. 
     
     
         6 . The method of  claim 5 , wherein the subject has elevated GDF15 activity in a body fluid. 
     
     
         7 . A method of treating or preventing congestive heart failure (CHF) in a subject in need thereof, the method comprising administering an effective amount of a composition that reduces or inhibits a GDF15 activity in the subject, thereby to treat or prevent CHF in the subject. 
     
     
         8 . The method of  claim 7 , wherein the subject has elevated GDF15 activity in a body fluid. 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . The method of any one of  claim 1 , wherein the subject exhibits a peak VO2 of less than less than 14 mL/kg/min. 
     
     
         12 . The method of any one of  claim 1 , wherein the subject exhibits an LVEF of less than 40%. 
     
     
         13 . The method of any one of  claim 1 , wherein the subject exhibits BNP levels in excess of 100 pg/ml. 
     
     
         14 . The method of any one of  claim 1 , wherein the subject exhibits serum cardiac troponin I (cTnI) levels in excess of 1.5 ng/mL. 
     
     
         15 . The method of any one of  claim 1 , wherein the subject has been diagnosed as having congestive heart failure. 
     
     
         16 . The method of any one of  claim 1 , wherein the GDF15 modulator reduces or inhibits GDF15 activity in the subject. 
     
     
         17 . The method of  claim 16 , wherein the GDF15 modulator binds GDF15. 
     
     
         18 . The method of  claim 17 , wherein the GDF15 modulator is an anti-GDF15 antibody. 
     
     
         19 . The method of  claim 18 , wherein the antibody is humanized or human. 
     
     
         20 . The method of  claim 1 , wherein the subject exhibits above normal levels of a marker selected from the group consisting of cardiac troponin I, cardiac troponin T, brain natriuretic protein (BNP), N-terminal peptides derived from BNP (NT-proBNP), and cardiac fatty acid binding protein (cFABP). 
     
     
         21 . The method of  claim 6 , wherein the body fluid is plasma or serum. 
     
     
         22 . The method of  claim 18 , wherein the anti-GDF15 antibody is selected from:
 a) an antibody comprising the heavy chain sequence of SEQ ID NO:47 and the light chain sequence of SEQ ID NO:30; and   b) an antibody comprising a heavy chain CDR H1  sequence of SEQ ID NO:1, a heavy chain CD H2  sequence of SEQ ID NO: 7, and a heavy chain CDR H3  sequence of SEQ ID NO:13; and a light chain CDR L1  sequence of SEQ ID NO:16, a light chain CDR L2  sequence of SEQ ID NO:18, and a light chain CDR L3  sequence of SEQ ID NO:22.