Regulation of apoB treatment and drug screening for cardiovascular and metabolic disorders or syndromes
OwnerEdward Fisher, Kevin Jon Williamsinventors
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Abstract
The present invention involves a method of exploiting a novel apolipoprotein-B (apoB) degradation pathway to regulate plasma levels of apoB to treat cardiovascular or metabolic disorders or syndromes, a method of exploiting a novel apolipoprotein-B (apoB) degradation pathway to screen for drugs to treat cardiovascular or metabolic disorders or syndromes, and a method of exploiting a novel apolipoprotein-B (apoB) degradation pathway to screen for genes for diagnosing cardiovascular or metabolic disorders or syndromes.
Claims24
A method of treating a patient, comprising administering a therapeutically effective amount of a Therapeutic to said patient, wherein said Therapeutic acts for a period of time to lower plasma concentrations of apoB and/or an apoB-containing lipoprotein and/or a component of an atherogenic lipoprotein by stimulating post-ER pre-secretory proteolysis (PERPP).
A method of screening a pharmaceutical compound, wherein said compound stimulates a PERPP that occurs in a post-ER compartment or compartments, comprising the steps of
- a) contacting hepatic cells with said compound;
- and
- b) measuring cellular content and/or secretion levels of an apoB, an apoB-containing lipoprotein and/or a component of an atherogenic lipoprotein to determine efficacy of said compound,
- wherein said method further comprises at least one of the steps of
- determining that a proteosome inhibitor does not substantially impair the efficacy of said compound;
- determining that heparin does not substantially impair the efficacy of said compound;
- determining that the efficacy of said compound is substantially reversible by an antioxidant;
- determining that the efficacy of said compound is substantially reversible by a PI-3 kinase inhibitor;
- determining that said compound does not substantially affect apoB level in the ER;
- and
- determining that said compound substantially increases cellular content of reactive oxygen species (ROS).
A method of screening for at least one gene, wherein said least one gene or RNA(s) or protein(s) encoded thereof regulate intracellular apoB degradation through PERPP, comprising the steps of
- a) preparing genetically engineered hepatic cells containing a mutation that affects said at least one gene;
- and
- b) measuring cellular content and/or secretion levels of an apoB, an apoB-containing lipoprotein, and/or a component of an atherogenic lipoprotein from said genetically engineered hepatic cells to determine that said at least one gene or said RNA(s) or protein(s) encoded thereof regulate said intracellular apoB degradation,
- wherein said method further comprises at least one of the steps of
- determining that a proteosome inhibitor does not substantially impair the regulation of intracellular apoB degradation by said at least one gene or said RNA(s) or protein(s) encoded thereof;
- determining that heparin does not substantially impair the regulation of intracellular apoB degradation by said at least one gene or said RNA(s) or protein(s) encoded thereof;
- determining that said genetically engineered hepatic cells exhibit substantially elevated or reduced apoB level in Golgi, but not ER;
- and
- determining that said genetically engineered hepatic cells exhibit substantially elevated or reduced cellular content of ROS.
A method of screening an HIV protease inhibitor, which exhibits reduced or absent inhibition of intracellular apoB degradation through PERPP, comprising the steps of
- a) contacting hepatic cells which exhibit PERPP with said HIV protease inhibitor;
- b) measuring cellular content and/or secretion levels of apoB, an apoB-containing lipoprotein and/or a component of an atherogenic lipoprotein to determine said reduced or absent inhibition of intracellular apoB degradation by said HIV protease inhibitor.
A method of treating an HIV-infected individual by administering a therapeutically effective amount of an HIV protease inhibitor, which inhibitor exhibits reduced or absent inhibition of intracellular apoB degradation.
A method of treating an HIV-infected individual by administering a first therapeutically effective amount of an HIV protease inhibitor and a second therapeutically effective amount of a compound, wherein said compound acts for a period of time to lower plasma concentrations of apoB, an apoB-containing lipoproteins, and/or a component of an atherogenic lipoprotein by stimulating PERPP.
Dependencies are inferred from the claim text.