Novel targets for treatment of hypercholesterolemia

Abstract

In certain embodiments this invention this invention pertains to the discovery that inhibition of myosin light chain interacting protein (Mylip) can mitigate one or more symptoms of hypercholesterolemia. Methods of treating hypercholesterolemia and methods of screening for agents to treat hypercholesterolemia are provided.

1 . A method of inhibiting LDL receptor degradation and/or promoting LDL uptake in a mammal, said method comprising administering an agent to said mammal that inhibits expression and/or activity of myosin light chain interacting protein (Mylip) in an amount sufficient to inhibit LDL receptor degradation and/or to promote LDL uptake in said mammal. 
     
     
         2 . A method of mitigating one or more symptoms of hypercholesterolemia in a mammal, said method comprising administering an agent to said mammal that inhibits expression and/or activity of myosin light chain interacting protein (Mylip) in an amount sufficient to mitigate one or more symptoms of hypercholesterolemia in said mammal. 
     
     
         3 . The method of  claim 1 , wherein Mylip expression and/or activity is inhibited in the liver of said mammal. 
     
     
         4 . The method of  claim 1 , wherein said mammal is a human. 
     
     
         5 . The method of  claim 4 , wherein said mammal is a human diagnosed as having or at risk for hypercholesterolemia. 
     
     
         6 . The method of  claim 1 , wherein said agent comprises an siRNA and/or an shRNA. 
     
     
         7 . The of  claim 1 , wherein said agent comprises a molecule that binds to the FERM domain of Idol and inhibits interaction or binding of Idol with LDLR. 
     
     
         8 . The method of  claim 7 , wherein said molecule inhibits interaction with or binding of Idol to the amino acid residues conserved between the amino acid residues conserved between LDLR, VLDLR and apoER2. 
     
     
         9 . The method of  claim 7 , wherein said molecule is an antibody that binds to the FERM domain of Idol and/or the amino acid residues conserved between the amino acid residues conserved between LDLR, VLDLR and apoER2. 
     
     
         10 . The of  claim 1 , wherein said agent is administered in a unit dosage formulation. 
     
     
         11 . The method of  claim 1 , wherein said agent is combined with an excipient suitable for administration to a human. 
     
     
         12 . The method of  claim 11 , wherein said excipient is sterile. 
     
     
         13 . A composition for inhibiting LDL receptor degradation and/or promoting LDL uptake in a mammal, said composition comprising an agent that inhibits Mylip expression and/or activity in a mammal, wherein said composition is formulated for administration to a mammal. 
     
     
         14 - 15 . (canceled) 
     
     
         16 . The composition of  claim 13 , wherein said agent comprises an siRNA and/or an shRNA. 
     
     
         17 . The composition of  claim 13 , wherein said agent comprises molecule that binds to the FERM domain of Idol and inhibits interaction or binding of Idol with LDLR 
     
     
         18 . The composition of  claim 17 , wherein said molecule inhibits interaction with or binding of Idol to amino acid residues conserved between LDLR, VLDLR and apoER2. 
     
     
         19 . The composition of  claim 17 , wherein said agent comprises an antibody that binds to the FERM domain of Idol and/or to amino acid residues conserved LDLR, VLDLR and apoER2. 
     
     
         20 . The composition of  claim 13 , wherein said agent is formulated with a carrier for administration to a human. 
     
     
         21 . The composition of  claim 13 , wherein said agent is formulated in a unit dosage formulation. 
     
     
         22 . The composition of  claim 13 , wherein said agent is formulated as a sterile formulation. 
     
     
         23 . A cell transfected with a construct encoding Idol, wherein said cell expresses Idol at a higher level than the same cell lacking said construct. 
     
     
         24 - 25 . (canceled) 
     
     
         26 . An non-human mammal comprising a cell transfected with a construct that expresses Idol, whereby said Idol is expressed at a higher level in a tissue of said animal than the same animal without said construct. 
     
     
         27 . (canceled) 
     
     
         28 . A non-human knockout mammal, the mammal comprising a disruption in an endogenous Mylip/Idol gene, wherein the disruption results in the mammal exhibiting a decreased level of Idol as compared to a wild-type mammal. 
     
     
         29 - 37 . (canceled) 
     
     
         38 . A method of screening for an agent that inhibits LDL receptor degradation and/or promotes LDL uptake in a mammal, said method comprising:
 contacting a cell with a test agent;   detecting the expression or activity of myosin light chain interacting protein (Mylip); and   scoring a decrease in Mylip expression or activity, as compared to the expression or activity of myosin light chain interacting protein (Mylip) in a control as an indication that said test agent is an agent that inhibits LDL receptor degradation and/or promotes LDL uptake in a mammal.   
     
     
         39 - 69 . (canceled) 
     
     
         70 . A method of screening for an agent that inhibits LDL receptor degradation and/or promotes LDL uptake in a mammal, said method comprising:
 contacting an Idol protein or a fragment thereof comprising the FERM domain with a test agent;   detecting binding of said test agent to said Idol protein or fragment thereof; and   scoring binding moieties as candidate agents that inhibit LDL receptor degradation and/or promote LDL uptake in a mammal.   
     
     
         71 . A method of screening for an agent that inhibits LDL receptor degradation and/or promotes LDL uptake in a mammal, said method comprising:
 contacting an LDLR or a fragment thereof comprising the amino acid residues that interact with Idol with a test agent;   detecting binding of said test agent to said LDLR or fragment thereof; and   scoring binding moieties as candidate agents that inhibit LDL receptor degradation and/or promote LDL uptake in a mammal.   
     
     
         72 . A method of screening for an agent that inhibits LDL receptor degradation and/or promotes LDL uptake in a mammal, said method comprising:
 contacting an LDLR or a fragment thereof comprising the amino acid residues that interact with Idol and/or an Idol protein or a fragment thereof comprising the FERM domain with a test agent;   detecting interaction or binding of the LDLR with said Idol protein or fragment; and   scoring moieties that reduce or block LDLR/Idol interaction or binding as candidate agents that inhibit LDL receptor degradation and/or promote LDL uptake in a mammal.   
     
     
         73 . A kit comprising a container containing a reporter cell wherein said reporter cell is transfected with a construct expressing an LDLR, and/or a construct expressing a Mylip. 
     
     
         74 - 76 . (canceled)