Modulation of the VPS10P-Domain Receptors for the Treatment of Cardiovascular Disease

Abstract

The present invention relates to methods for modulating the activity of one or more Vps10p-domain receptors selected from the group consisting of Sortilin, SorLA, SorCS1, SorCS2 and SorCS3, in an animal and methods for preparation of a medicament for the treatment of abnormal plasma lipid concentrations and associated diseases and/or disorders. The modulation is carried out by inhibiting or promoting the binding of ligands to the Vps10p-domain receptor. In vitro and in vivo methods for screening for agents capable of modulation of said Vps10p-domain receptor activity are also provided. The invention furthermore relates to methods of altering expression of said receptors in vivo.

1 . An antibody for use in a method of treatment and/or prevention of abnormal plasma lipid concentrations in an animal, wherein said antagonist is capable of binding to a receptor of Sortilin thus inhibiting the activity of said Sortilin receptor. 
     
     
         2 . The antibody of  claim 1  wherein said abnormal plasma lipid concentrations is hyperlipoproteinemia. 
     
     
         3 . The antibody of  claim 2  wherein the hyperlipoproteinemia is selected from the group consisting of Buerger-Gruetz syndrome, Primary hyperlipoproteinaemia, Familial hyperchylomicronemia, polygenic hypercholesterolemia, combined hyperlipidemia, familial Dysbetalipoproteinemia, endogenous Hyperlipemia, familial Hypertriglyceridemia, Aneurysm, Angina pectoris, Atherosclerosis, Cerebrovascular Accident (Stroke), Cerebrovascular disease, Congenital heart disease, Congestive Heart Failure, Coronary Artery Disease, Dilated cardiomyopathy, Diastolic dysfunction, Endocarditis, Hypercholesterolemia, Hypertension, Hyperlipidemia, Hypertrophic cardiomyopathy, Mitral valve prolapse, Myocardial infarction (Heart Attack) and Venous Thromboembolism. 
     
     
         4 . The antibody according to  claim 1  wherein said antibody is capable of inhibiting binding of an agonist selected from the group consisting of ApoB, proNGF, proBDNF, proNT3, pro-NT4/5, ApoE or LpL or a fragment or variant thereof, to said Sortilin receptor. 
     
     
         5 . The antibody according to  claim 1 , wherein the animal is a human being. 
     
     
         6 . The antibody according to  claim 1  wherein said antibody is selected from the group consisting of: polyclonal antibodies, monoclonal antibodies, humanised antibodies, single chain antibodies, recombinant antibodies. 
     
     
         7 . The antibody according to  claim 1 , wherein the antibody is directed against the extracellular part of Sortilin. 
     
     
         8 . The antagonist according to  claim 1 , wherein the antagonist binds at least one amino acid residue of the binding site comprising amino acid residues R325, S316, Y351, I353, K260, I327, F314, F350 to M363, S305, F306, T398 to G400, I303-G309, Q349-A356, Y395 and T402 of SEQ ID NO. 1 or a fragment or variant thereof. 
     
     
         9 . The antagonist according to  claim 1 , wherein the antagonist binds at least one amino acid residue of the binding site comprising amino acid residues L572, L114, V112, R109 to S111, S115 to G118, T570, G571, W586, W597, T168-I174, L572, A573 and S584 to F588 of SEQ ID NO. 1 or a fragment or variant thereof.