TREATMENT OF CONGESTIVE HEART FAILURE AND OTHER CARDIAC DYSFUNCTION USING A GDF15 MODULATOR
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.