Methods and compositions relating to leptin antagonists

Abstract

Devices, methods and compositions for treating cardiovascular disorders are configured for sustained-release of leptin antagonist into a blood vessel in order to down-regulate an expression or activity of leptin in a cardiovascular tissue that is affected by a disorder.

What is claimed is: 
     
         1 . A method of treating a cardiovascular disorder comprising:
 locally administering a leptin antagonist to a cardiovascular tissue affected by said cardiovascular disorder for down-regulating an expression or activity of leptin in said cardiovascular tissue, wherein said leptin antagonist is a modified mammalian leptin peptide capable of binding a leptin receptor.   
     
     
         2 . The method of  claim 1 , wherein said leptin antagonist is selected from the group consisting of (a) a modified mammalian leptin peptide comprising a mammalian leptin polypeptide in which the LDFI hydrophobic binding site at the positions corresponding to positions 39-42 of the wild-type human leptin (SEQ ID NO:1) is modified such that from two to four amino acid residues of said hydrophobic binding site are substituted with different amino acid residues such that the site becomes less hydrophobic; (b) the modified mammalian leptin polypeptide according to (a) in which the aspartic acid at the position corresponding to position 23 od the wild-type human leptin (D23) is substituted with an amino acid residue selected from the group consisting of glycine, alanine, leucine, lysine, arginine, phenylalanine, tryptophan and histidine, or in which the threonine at the position corresponding to position 12 of the wild-type human leptin (T12) is substituted with a different amino acid residue that is hydrophobic; and (c) a pharmaceutically acceptable salt of (a) or (b). 
     
     
         3 . The method of  claim 1 , wherein said leptin antagonist wherein said modified mammalian leptin peptide is of an amino acid sequence selected from SEQ ID NOs: 3-10, 36 and 38 
     
     
         4 . The method of  claim 1 , wherein said cardiovascular disorder is characterized by tissue remodeling. 
     
     
         5 . The method of  claim 1 , wherein said cardiovascular disorder is selected from the group consisting of vascular aneurysm, aortic aneurysm, atherosclerotic plaques, left ventricular remodeling, myocardial infarction, myointimal hyperplasia, vascular injury, left heart failure and aortic or mitral valve disease. 
     
     
         6 . The method of  claim 1 , wherein said cardiovascular disorder is selected from the group consisting of cardiovascular disease; remodeling of stable athersclerotic plaque into an unstable lesion; ascending aortic aneurysm associated with hypertension, dyslipidemia, hypercholesterolemia, obesity, diabetes mellitus or bicuspid aortic valve; Takayasu disease; rheumatoid arteritis; giant cell arteritis; inflammatory aortic aneurysm; thoracic aortic aneurysm; abdominal aortic aneurysm; aortic aneurysm and/or pulmonary artery aneurysm in Marfan syndrome; aortic dissection in an aortic or peripheral large artery; angiogenesis; and arteriovenous malformation. 
     
     
         7 . The method of  claim 1 , wherein said cardiovascular tissue is arterial or venous wall tissue. 
     
     
         8 . The method of  claim 1 , wherein said cardiovascular tissue is aortic and/or mitral heart valve leaflet tissue. 
     
     
         9 . The method of  claim 1 , wherein said cardiovascular tissue is an inner (luminal) surface of an aorta or an outer wall of an aorta, within or on the surface of a vascular organ. 
     
     
         10 . The method of  claim 1 , wherein said locally administrating is effected by means of a carrier configured for localized release of said leptin antagonist. 
     
     
         11 . The method of  claim 1 , wherein said locally administrating is effected via direct injection. 
     
     
         12 . The method of  claim 10 , wherein said carrier is a solid, gel or liquid carrier. 
     
     
         13 . The method of  claim 10 , wherein said carrier comprises a biodegradable support. 
     
     
         14 . The method of  claim 10 , wherein said carrier is configured as a film. 
     
     
         15 . The method of  claim 10 , wherein said carrier is a device selected from the group consisting of a gel, mesh, a balloon and a vascular graft. 
     
     
         16 . The method of  claim 10 , wherein said carrier is a depot-forming injectable composition. 
     
     
         17 . The method of  claim 10 , wherein said carrier is a scaffold configured for slow release and said cardiovascular tissue is the luminal surface of an aorta, and wherein said scaffold for slow release is applied to said luminal surface of the aorta via arterial catheterization. 
     
     
         18 . The method of  claim 17 , wherein said scaffold is biodegradable. 
     
     
         19 . The method of  claim 1 , wherein said locally administrating is effected intracavitarily.