Methods and compositions for treatment of atherosclerosis

Abstract

The present invention provides methods and compositions for treating atherosclerosis in a subject comprising the use of therapeutic compounds to reduce Reelin in the circulation of the subject, thereby reducing the adhesion of leukocytes to the vascular wall. The invention also provides methods and compositions for reducing leukocyte adhesion to the vascular wall in a subject.

What is claimed is: 
     
         1 . A method of treatment or prevention of atherosclerosis in a subject comprising providing to a subject an amount of a therapeutic composition effective to decrease the activity of Reelin in the circulation of the subject, wherein said treatment or prevention results in a reduction of disease symptoms in the subject. 
     
     
         2 . The method of  claim 1 , wherein said reduction of disease symptoms comprises reduced leukocyte adhesion to the vascular wall in the subject. 
     
     
         3 . The method of  claim 1 , wherein said decreased activity of Reelin comprises reduction of Reelin protein expression or inhibition of Reelin function in the circulation of a subject. 
     
     
         4 . The method of  claim 1 , wherein said therapeutic composition comprises a protein, a peptide, a polypeptide, an RNA molecule, a peptidomimetic that inhibits Reelin oligomerization or receptor binding, an siRNA molecule, a decoy receptor, a carbohydrate, an antibody or antibody fragment, or a small molecule, wherein said therapeutic composition targets Reelin, resulting in a reduction of Reelin activity in the circulation of the subject. 
     
     
         5 . The method of  claim 4 , wherein the antibody is a monoclonal antibody. 
     
     
         6 . The method of  claim 4 , wherein the antibody is a humanized antibody. 
     
     
         7 . The method of  claim 4 , wherein the decoy receptor is an Fc-coupled dimeric or monomeric decoy receptor. 
     
     
         8 . The method of  claim 1 , wherein said therapeutic composition performs a function comprising:
 (a) reducing or inhibiting the expression of a gene encoding Reelin;   (b) reducing or inhibiting the expression of a Reelin protein;   (c) reducing or inhibiting expression of a receptor for Reelin;   (d) reducing or inhibiting the function of a Reelin protein; or   (e) binding to Reelin protein in such a way that the function is reduced or eliminated.   
     
     
         9 . The method of  claim 1 , further comprising administering an antithrombotic drug, an antibody targeting PCSK9, or an HMG-CoA reductase inhibitor to the subject. 
     
     
         10 . A method for reducing leukocyte adhesion to the vascular wall in a subject, comprising administering to the subject a therapeutic compound targeting Reelin in the circulation of the subject, wherein said treatment results in reduced leukocyte adhesion to the vascular wall. 
     
     
         11 . The method of  claim 10 , wherein said targeting Reelin comprises reduction of Reelin protein expression or inhibition of Reelin function in the circulation of a subject. 
     
     
         12 . The method of  claim 10 , wherein said therapeutic compound comprises a protein, a peptide, a polypeptide, an RNA molecule, a peptidomimetic that inhibits Reelin oligomerization or receptor binding, an siRNA molecule, a decoy receptor, a carbohydrate, an antibody or antibody fragment, or a small molecule, wherein said therapeutic compound targets Reelin, resulting in reduced leukocyte adhesion to the vascular wall of the subject. 
     
     
         13 . The method of  claim 12 , wherein the antibody is a monoclonal antibody. 
     
     
         14 . The method of  claim 12 , wherein the decoy receptor is an Fc-coupled dimeric or monomeric decoy receptor. 
     
     
         15 . The method of  claim 10 , wherein said therapeutic compound performs a function comprising:
 (a) reducing or inhibiting the expression of a gene encoding Reelin;   (b) reducing or inhibiting the expression of a Reelin protein;   (c) reducing or inhibiting expression of a receptor for Reelin;   (d) reducing or inhibiting the function of a Reelin protein; or   (e) binding to Reelin protein in such a way that the function is reduced or eliminated.   
     
     
         16 . The method of  claim 10 , further comprising administering an antithrombotic drug, an antibody targeting PCSK9 or an HMG-CoA reductase inhibitor to the subject. 
     
     
         17 . The method of  claim 10 , further comprising identifying a subject suspected of having atherosclerosis or being in need of atherosclerosis treatment. 
     
     
         18 . A therapeutic composition for treating atherosclerosis in a subject comprising a therapeutic compound in an effective amount to reduce disease symptoms and a non-natural, pharmaceutically acceptable carrier. 
     
     
         19 . The composition of  claim 18 , wherein the therapeutic compound comprises a protein, a peptide, a polypeptide, an RNA molecule, an siRNA molecule, a decoy receptor, a carbohydrate, an antibody or antibody fragment, or a small molecule, wherein said therapeutic compound targets Reelin, resulting in a reduction of Reelin in the circulation of the subject. 
     
     
         20 . A human or humanized antibody, fragment, or derivative thereof which recognizes Reelin, for the treatment of atherosclerosis, or diseases associated therewith or resulting therefrom. 
     
     
         21 . A pharmaceutical composition comprising an siRNA complementary to all or a portion of a Reelin mRNA sequence (SEQ ID NO:3-5). 
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein the siRNA functions to inhibit Reelin in a subject. 
     
     
         23 . A method of treatment or prevention of multiple sclerosis, arthritis, or psoriasis in a subject comprising providing to a subject an amount of a therapeutic composition effective to decrease the activity of Reelin in the circulation of the subject, wherein said treatment or prevention results in a reduction of disease symptoms in the subject.