Diagnosis, prevention, and/or treatment of atherosclerosis and underlying and/or related diseases

Abstract

Complement is recognized as an important, humoral defense system involved in the innate (nonspecific) recognition and elimination of microbial invaders, other foreign particles or molecules, and antigen-antibody complexes from the body. The present invention makes use of the surprising notion that the handling of lipids by the body, rather than its antimicrobial activity, is the primary and most ancient function of the complement system. Consequently, atherosclerosis as observed in disorders associated with disturbed lipid metabolism (familial combined hyperlipidemia (FCHL), postprandial hyperlipidemia, hypertriglyceridemia with low levels of HDL cholesterol, and insulin resistance associated with type-II diabetes and obesity), is ascribed to either genetic or acquired defects in ancient (activatory and/or regulatory) complement components. Based on this new insight, novel preventive measures and treatment modalities of disturbed lipid metabolism are introduced.

1 . A method for the treatment and/or prophylaxis of diseases associated with disturbances in the complement/lipid pathway, said method comprising:
 modulating the activity of one or more elements in the complement/lipid pathway of a subject.   
   
   
       2 . The method according to  claim 1 , wherein the activity of one or more elements of a lectin pathway, a classical pathway and/or an alternative pathway for complement activation are modulated. 
   
   
       3 . The method according to  claim 1 , wherein the disease is atherogenic. 
   
   
       4 . The method according to  claim 1 , wherein the disease is atherosclerosis and/or an underlying and/or related disease. 
   
   
       5 . The method according to  claim 1 , wherein said modulating the activity of one or more elements is achieved through administering one or more modulators to the subject. 
   
   
       6 . The method according to  claim 5 , wherein the modulator is selected from the group consisting of MBL and MBL-replacement factors, C4A, C4B, C2, C3, IgG- and IgM-antibodies raised against triglyceride-rich particles and LDL or parts thereof, C3adesArg, factor B, factor D, factor P, serum carboxypeptidases, sCP-N, erythrocyte-bound CR1, free CR1, CR1 mimetics, C3b antibodies, vitronectin, clusterin, and apo B (48 and 100) and apo B replacement factors, esterases, an MASP-protein, and a functional equivalent or mixture of any thereof. 
   
   
       7 . The method according to  claim 5 , wherein the modulator is selected from the group consisting of MBL-replacement factors and apo B replacement factors. 
   
   
       8 . The method according to  claim 1 , wherein said modulator is an antibody. 
   
   
       9 . The method according to  claim 8 , where said antibody is selected from the group consisting of IgG antibodies, IgM antibodies, and mixtures thereof. 
   
   
       10 . The method according to  claim 6 , wherein the modulator comprises apo B replacement factors and a heavily mannosylated IgA or IgD antibody directed against an apo B lipoprotein. 
   
   
       11 . The method according to  claim 6 , wherein the modulator comprises apo B replacement factors and a heavily N-acetylglucosaminylated IgA or IgD antibody directed against an apo B lipoprotein. 
   
   
       12 . The method according to  claim 6 , wherein the modulator comprises apo B replacement factors and a heavily fucosylated IgA or IgD antibody directed against an apo B lipoprotein. 
   
   
       13 . The method according to  claim 8 , wherein said antibody is selected from the group consisting of polyclonal antibodies, humanized monoclonal antibodies, combinatorial antibody, and mixtures thereof. 
   
   
       14 . The method according to  claim 8 , wherein said antibody comprises bi-specific antibodies reactive towards both an apo B and CR1. 
   
   
       15 . The method according to  claim 5 , wherein the modulator is administered via parenteral feeding in an intralipid carrier. 
   
   
       16 . The method according to  claim 15 , wherein the intralipid carrier is olive oil. 
   
   
       17 . The method according to  claim 5 , wherein the modulator is generated in vivo in the subject. 
   
   
       18 . The method according to  claim 1  for the treatment and/or prophylaxis of diseases selected from the group consisting of diseases associated with impaired complement-dependent lipid metabolism, atherosclerosis and/or underlying and/or related diseases, and atherogenic processes of concomitant (infectious, autoimmune, or neoplastic) diseases that at least partially occupy the lipid eliminating complement activation pathway. 
   
   
       19 . A method for diagnosing disturbances in the complement/lipid pathway or an underlying or related defect of atherosclerosis, said method comprising:
 determining the presence and/or abundance of at least one element of the complement/lipid pathway in a sample.   
   
   
       20 . (canceled) 
   
   
       21 . The method according to  claim 19 , wherein said at least one element of the complement/lipid pathway is selected from the group consisting of MBL, C4A, C4B, C2, factor B, factor D, C3adesArg, serum carboxypeptidase N, vitronectin, clusterin, chylomicron-bound sialic acid, and erythrocyte-bound complement receptor 1 (CR1). 
   
   
       22 . The method according to  claim 21 , wherein additionally at least one concomitant (infectious, autoimmune, or neoplastic) disease that may at least partially occupy the lipid eliminating complement activation pathway is diagnosed. 
   
   
       23 . The method according to  claim 21 , wherein additionally a subject's lipid profile is determined by using whole blood. 
   
   
       24 . The method according to  claim 21 , for discovering pharmaceutical and/or nutritional compounds for the treatment and/or prophylaxis of atherogenic disturbances of lipid metabolism related to disturbances in the complement/lipid pathway. 
   
   
       25 . (canceled) 
   
   
       26 . A composition for the treatment and/or prophylaxis of diseases selected from the group consisting of diseases associated with disturbances in the complement/lipid pathway, atherosclerosis and/or an underlying and/or a related disease associated with disturbances in the complement/lipid pathway, and disturbances of lipid metabolism, said composition comprising:
 at least one modulator of the complement/lipid pathway.   
   
   
       27 . The composition of  claim 26 , wherein said composition modulates the activity of one or more elements of the lectin pathway and/or the alternative pathway for complement activation. 
   
   
       28 . The composition of  claim 26 , wherein said modulator is selected from the group consisting of MBL and MBL-replacement factors, C4A, C4B, C2, C3, IgG- and IgM-antibodies raised against triglyceride-rich particles and LDL or parts thereof, C3adesArg, factor B, factor D, factor P, serum carboxypeptidases, sCP-N, erythrocyte-bound CR1, free CR1, CR1 mimetics, C3b antibodies, vitronectin, clusterin, apo B (48 and 100) and apo B replacement factors, esterases, an MASP-protein, and functional equivalents and mixtures of any thereof. 
   
   
       29 . The composition of  claim 26 , wherein said modulator is selected from the group consisting of MBL-replacement factors and apo B replacement factors. 
   
   
       30 . The composition of  claim 26 , wherein said modulators are metabolic precursors of modulators. 
   
   
       31 . The composition of  claim 26 , further comprising a pharmaceutically acceptable carrier selected from the group consisting of natural lipid carriers, artificial lipid carriers, synthetic lipid carriers, mineral oil, natural oil, processed mineral oil, natural oil, and mixtures thereof. 
   
   
       32 . A kit for diagnosing atherogenic disturbances of lipid metabolism or diagnosing atherosclerosis by a method according to any of the  claims 18 , said kit comprising:
 means for receiving a sample, and   means for carrying out an assay for the detection of at least one modulator and/or element of the complement/lipid pathway in the sample.