Modulation of the Vps10p-domain for the treatment of cardiovascular disease

摘要

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.

主权项

1. A method for identifying a desired antagonist for regulating plasma lipid concentrations, comprising the steps of:
(1)(a) incubating cells that express a Vps10p-domain receptor that comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO:1 (Sortilin), said cells being in an in vitro cell culture, in the presence of a Vps10p-domain receptor agonist under conditions sufficient to permit:
(i) agonist binding to said Vps10p-domain receptor;(ii) agonist internalization by said Vps10p-domain receptor; or(iii) agonist-promoted signalling by said Vps10p-domain receptor;wherein said cells and said agonist are further incubated in the presence of a candidate antagonist; (1)(b) determining whether the presence of said candidate antagonist affects:
(i) the extent of binding between said Vps10p-domain receptor and said agonist;(ii) the extent of agonist internalization by said Vps10p-domain receptor; or(iii) the extent of agonist-promoted signalling by said Vps10p-domain receptor,wherein a decrease in the extent of said binding, said internalization or said signalling observed in the presence of said candidate antagonist relative to the extent of said binding, said internalization or said signalling occurring in the absence of said candidate antagonist identifies said candidate antagonist as being capable of inhibiting an activity of said Vps10p-domain receptor; (2)(a) administering said candidate antagonist to an animal expressing said Vps10p-domain receptor; and (2)(b) determining whether administration of said candidate antagonist to said animal alters the level of plasma cholesterol as compared to a control animal expressing said Vps10p-domain receptor, wherein said control animal is not administered said candidate antagonist, wherein a difference in the level of plasma cholesterol between said animal administered said candidate antagonist and said control animal identifies said candidate antagonist as being a desired antagonist capable of regulating plasma lipid concentrations, and wherein said agonist is SEQ ID NO:6 (proNGF) or a polypeptide having at least 95% sequence identity to SEQ ID NO:6.