Methods for cardioprotection and cardioregeneration with dimers of egf family ligands

Abstract

The invention provides methods and compositions for reducing, preventing or reversing cardio toxicity side effects associated with certain therapeutic agents. The invention also provides methods and compositions for treating heart dysfunction including heart failure, and for reversing the effects of myocardial infarction. The various aspects of the invention involve the use of ligand dimers, such as neuregulin dimers, that selectively induce the dimerization of certain EGF receptors in cardiac tissue.

1 . A method for reducing anthracycline-associated cardiotoxicity comprising
 administering to a subject, in need of anthracycline therapy, a neuregulin dimer or a ligand dimer in an amount effective to reduce anthracycline-associated cardiotoxicity, wherein the ligand dimer comprises an epidermal growth factor (EGF) ligand, a neuregulin ligand, or a spitz ligand.   
     
     
         2 . The method of  claim 1 , wherein the anthracycline therapy is doxorubicin. 
     
     
         3 . The method of  claim 1 , wherein the subject is administered the neuregulin dimer prior to the anthracycline therapy. 
     
     
         4 . The method of  claim 1 , wherein the subject is administered the neuregulin dimer after the anthracycline therapy. 
     
     
         5 . The method of  claim 1 , wherein the neuregulin dimer is administered locally to the heart. 
     
     
         6 . The method of  claim 1 , wherein the subject is administered an amount of anthracycline therapy above the normally administered amount. 
     
     
         7 . The method of  claim 1 , wherein the neuregulin dimer is administered in a sustained release formulation. 
     
     
         8 . (canceled) 
     
     
         9 . The method of  claim 1 , wherein the ligand dimer is an EGF dimer. 
     
     
         10 . The method of  claim 1 , wherein the ligand dimer is a spitz dimer. 
     
     
         11 . The method of  claim 1 , wherein the ligand dimer comprises a neuregulin ligand and an EGF ligand. 
     
     
         12 . The method of  claim 1 , wherein the ligand dimer comprises a spitz ligand and a neuregulin ligand. 
     
     
         13 . The method of  claim 1 , wherein the ligand dimer comprises a spitz ligand and an EGF ligand. 
     
     
         14 - 19 . (canceled) 
     
     
         20 . A method for increasing anthracycline tolerable dose comprising administering to a subject in need of anthracycline therapy:
 a neuregulin dimer and an anthracycline, wherein the anthracycline is administered in an amount above the normally administered amount; or   a ligand dimer and an anthracycline, wherein the ligand dimer comprises an epidermal growth factor (EGF) ligand, a neuregulin ligand, or a spitz ligand, and wherein the anthracycline is administered in an amount above the normally administered amount.   
     
     
         21 - 30 . (canceled) 
     
     
         31 . The method of  claim 20 , wherein the anthracycline therapy is administered in an amount that is about 10% above the normally administered amount. 
     
     
         32 . The method of  claim 20 , wherein the anthracycline therapy is administered in an amount that is about 25% above the normally administered amount. 
     
     
         33 - 38 . (canceled) 
     
     
         39 . A method for treating a subject comprising
 administering to a subject who is experiencing or has experienced a myocardial infarction, or who is having heart failure:   a neuregulin dimer or a ligand dimer in an amount effective to reduce infarct size, wherein the ligand dimer comprises an epidermal growth factor (EGF) ligand, a neuregulin ligand, or a spitz ligand.   
     
     
         40 - 58 . (canceled) 
     
     
         59 . A ligand dimer, comprising two ligands, at least one of which is a spitz ligand, and a linker, wherein the ligand dimer causes dimerization of receptors at least one of which is a HER receptor. 
     
     
         60 - 69 . (canceled) 
     
     
         70 . A composition comprising the ligand dimer of  claim 59 , wherein the ligand dimer is attached to a substrate. 
     
     
         71 - 72 . (canceled) 
     
     
         73 . A ligand dimer, comprising two ligands, wherein the ligand dimer causes oligomerization or aggregation of receptors, at least one of which is a HER receptor. 
     
     
         74 - 78 . (canceled)