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  Cholesterol transport geneUSPTO Application #: 20070298420Title: Cholesterol transport gene Abstract: Methods and compounds are disclosed for lowering serum LDL levels or serum cholesterol levels, or for reducing the transport of cholesterol from the gut to the blood or the lymph, based on the observation that a gene known as ABC1 is necessary in order for cholesterol to be transported from the intestinal lumen into the bloodstream. A mutant chicken phenotype, known as the WHAM chicken, characterized by low levels of serum LDL and reduced transport of cholesterol, facilitated the discovery of this function of the ABC1 gene. Techniques which act to inhibit ABC1 activity in the cells of the intestinal wall will result in lower serum cholesterol. (end of abstract) Agent: Quarles & Brady LLP - Madison, WI, US Inventors: Alan D. Attie, Mark Cook, Mark P. Gray-Keller, Michael R. Hayden, Simon Pimstone, Angela R. Brooks-Wilson USPTO Applicaton #: 20070298420 - Class: 435006000 (USPTO) Related Patent Categories: Chemistry: Molecular Biology And Microbiology, Measuring Or Testing Process Involving Enzymes Or Micro-organisms; Composition Or Test Strip Therefore; Processes Of Forming Such Composition Or Test Strip, Involving Nucleic Acid The Patent Description & Claims data below is from USPTO Patent Application 20070298420. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS REFERENCE TO RELATED APPLICATION [0001] This application claims the benefit of U.S. Provisional patent applications Ser. No. 60/162,803 filed Nov. 1, 1999 and Ser. No. 60/215,564 filed Jun. 20, 2000. BACKGROUND OF THE INVENTION [0002] Cholesterol is one of the most intensely studied of molecules that circulate in the human bloodstream. Cholesterol is a lipid that is a major component of cell membranes and also is the precursor of steroid hormones and the bile acids. Two sources of cholesterol are available to cells. Endogenous cholesterol is synthesized in the liver and other cells and transported through the bloodstream to other cells. Since cholesterol is highly apolar, it is transported through the bloodstream in the form of lipoproteins consisting essentially of a core of apolar molecules such as cholesterol surrounded by an envelope of polar lipids, primarily phospholipids. Alternatively, exogenous cholesterol may be absorbed from the gut. Exogenous cholesterol is transported from the lumen of the gut into the blood or lymph for distribution via lipoprotein particles to other cells of the body. [0003] For the diagnostic purposes related to human health, the lipoproteins are classified into several categories based on the density of the lipoprotein particles. The two categories most discussed in connection with human health are the low-density lipoproteins (LDL) and the high-density lipoproteins (HDL). For many people, HDL is known as the "good cholesterol" since it has a somewhat protective effect on the tendency of LDL to contribute toward coronary artery disease and related cardiovascular conditions such as stroke. Studies have shown an inverse relationship between levels of serum HDL and the occurrence of coronary artery disease, resulting in HDL levels being graded as a strong risk factor for cardiovascular disease prediction. Accordingly, a low level of HDL cholesterol, referred to as hypoalphalipoproteinemia, is a blood abnormality that correlates with increased risk of cardiovascular disease. [0004] One rare form of genetic HDL deficiency is known as Tangier disease. Patients with the homozygous form of this disease have an almost total absence of serum HDL cholesterol. The disease is an autosomal recessive trait, and patients with the disease accumulate cholesterol esters in several tissues, resulting in characteristic physical features including enlarged orange or yellow tonsils, hepatosplenomegaly, peripheral neuropathy, and cholesterol deposition in the rectal mucosa. The symptoms of the disease appear to be attributable to a deficiency in cholesterol and/or phospholipid transport across cell membranes, principally out of cells that manufacture or store excess cholesterol. The orange tonsils are, for example, caused by the accumulation of cholesterol esters and related carotenoids in macrophages. It has now been established that Tangier Disease is a monogenic disorder caused by a mutation in the ABC1 gene (Brooks-Wilson, A. et al. 1999, "Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency." Nat. Genet. 22:336-345; Bodzioch, M. et al. 1999, "The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier Disease." Nat. Genet. 22:347-351; Rust, S., et al. 1999, "Tangier Disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1." Nat. Genet. 22:352-355). Other patients exhibit a more common form of genetic HDL deficiency which results in low plasma HDL and premature cardiovascular disease, but an absence of the severe symptoms associated with Tangier disease. A large sub-group of patients with low HDL have an inherited form of this disease, familial hypoalphalipoproteinemia (FHA). It has been found that many of these patients are heterozygotes for mutations in ABC1. (Brooks-Wilson, A. et al. 1999, supra). Thus, ABC1 in its homozygous form causes Tangier disease and in its heterozygous form causes FHA. [0005] An animal model for low HDL conditions exists in the form of the Wisconsin Hypo-Alpha Mutant (WHAM) chicken. This single gene mutation arose naturally and was identified because of the white skin phenotype and a closed flock of the chickens has been maintained as an animal model for low HDL disease. (Poernama et al. Jour. Lipid Res. 31:955-963 (1990)). The effect of this mutation on diet-induced atherosclerosis has been investigated, and it has been found that WHAM chickens are highly deficient in their ability to transport cholesterol from the gut into the blood. (Poernama et al. Arteriosclerosis and Thrombosis 12:2:601-607 (1992)). Some efforts have been made to identify the genetic element responsible for the mutation in the WHAM chickens (Schreyer et al. Arteriosclerosis and Thrombosis 14:12:2053-2059 (1994)), but prior to the instant invention, these efforts have not been successful. [0006] It is highly desirable to identify and develop compounds and therapeutic agents which are useful for reducing cholesterol transport from the gut to the blood or lymph and for the regulation and treatment of cardiovascular disorders (such as high LDL or serum cholesterol levels), obesity, elevated body-weight index and other disorders relating to lipid metabolism. SUMMARY OF THE INVENTION [0007] The present invention is summarized in that a method is described for the lowering of levels of LDL cholesterol in an individual comprising administering to the individual an agent which modulates the activity of the ABC1 protein in the intestinal cells of the individual. [0008] The present invention is further summarized in that a method is described for reducing cholesterol transport from the gut into the blood or lymph comprising administering a modulator of the ABC1 protein. In a preferred embodiment, the modulator is an inhibitor of ABC1 activity, and it is administered orally. [0009] The present invention is also summarized in that a method for screening drug candidates for lowering serum LDL levels or for reducing cholesterol transport from the gut into the blood or lymph includes the steps of screening compounds for the effect of modulating ABC1 protein activity. In a preferred embodiment, the modulator is an inhibitor of ABC1 activity. In a further embodiment, successful candidates are further screened for the effect of not stimulating insulin production. Successful drug candidates may optionally be further modified by combinatorial chemistry to generate preferred therapeutic agents. [0010] Compositions of the invention include compounds which are useful for reducing cholesterol transport from the gut to the blood or lymph and for the regulation and treatment of cardiovascular disorders (such as high LDL or serum cholesterol levels), obesity, elevated body-weight index and other disorders relating to lipid metabolism which are identified using the screening assays of the invention. [0011] Other objects, advantages and features of the present invention will become apparent from the following specification. BRIEF DESCRIPTION OF THE DRAWING FIGURES [0012] FIG. 1 is a graphical illustration of the relationship between the human ABC1 gene and the mutation responsible for the phenotype of the WHAM chickens. [0013] FIG. 2 is a graphical representation of some of the data from an example below. [0014] FIG. 3 is an electro-micrograph of the intestinal wall demonstrating accumulation of giant lipid droplets in WHAM chickens but not control chickens. The lipids are not found in columnar epithelial cells, but in deeper underlying cells of the lamina propria. [0015] FIG. 4 is a graphical representation of data which demonstrates the response to dietary cholesterol in normal and WHAM chickens DETAILED DESCRIPTION OF THE INVENTION [0016] The insights that gave rise to the present invention derive from several sources. One is the recent identification by several of the inventors of the specific human gene responsible for Tangier disease. That gene was identified to be a gene known as ABC1, a gene that is part of the ATP-binding cassette superfamily of genes. Deficiencies in the function of this gene are associated with decreased transport of cholesterol out of cells that synthesize excess cholesterol. The second insight was the understanding that the genetic mutation in the WHAM chickens is, in fact, a mutation in the same ABC1 gene or a related gene. This insight establishes for the first time that the ABC1 protein may be critical for cholesterol absorption. Because the mechanism of action of the mutant gene in the WHAM chickens had been previously understood to be a deficiency in absorption of isoprenoids and sterols from the lumen of the digestive tract, this observation suggested to the inventors that the same ABC1 gene may be necessary for cholesterol transport from the digestive tract to the blood stream. The combination of these two observations had led to the understanding, first expressed here, that lowered serum cholesterol levels, and in particular, lower levels of LDL, of "bad" cholesterol, can be achieved by blocking the transport action of the ABC1 in facilitating the transport of cholesterol from the intestinal lumen through the intestinal wall cells into the blood stream. Since it is revealed here that the ABC1 gene is a necessary component in the transport of isoprenoids and sterols from the gut into the blood stream, as revealed in particular by the inability of WHAM chickens to uptake these compounds from their diets, it also becomes clear that uptake of these compounds in healthy individuals from the intestines can also be inhibited by blocking the action of otherwise functional copies of this transport protein. Since cholesterol in the intestinal tract is either secreted by the liver into the bile and thus into the intestinal tract, or derives from exogenous sources, blocking the absorption of cholesterol from the gut into the blood stream through the intestinal wall will result in lowering the total level of cholesterol in the plasma of the individual. [0017] The ABC1 protein is a cross-membrane transport protein. In cells throughout the body, the protein transports cholesterol from the cytosol into the blood stream. In the cells of the intestinal wall, this transport protein performs a similar function. Cholesterol is absorbed from the intestinal lumen into the cells lining the intestinal wall and is then transported into the blood stream. In the absence of an effective ABC1 protein, the cholesterol can not be transported into the blood or lymph and can go no further. Thus, in ABC1 deficient individuals, cholesterol accumulates in the wall of the intestines. In individuals with normal ABC1 protein function, the ABC1 protein serves to transport the cholesterol absorbed from the intestine from the cell into the blood stream. Thus inhibiting the transport function of the ABC1 protein in intestinal wall cells prevents cholesterol entering the gut from being transported into the blood stream. [0018] This invention establishes for the first time the presence of a two stage process for cholesterol absorption from the gut: cholesterol first proceeds to cross the epithelial cells; and secondly by an ABC1-dependent process cholesterol is transported through the lamina propria into the blood or lymph. Thus an important aspect of this invention is the identification of a layer of cells beneath the columnar epithelium which are an essential part of the cholesterol absorption/transport pathway. These cells can be studied for other mechanisms or sites of activity for compounds which lead to inhibition of cholesterol absorption/transport from the gut to the blood. [0019] This insight leads to other useful processes. Since the same gene, ABC1, is responsible for transport of cholesterol, phospholipids and other isoprenoids, including carotenoids, from intestinal wall cells into the blood stream, assays for the ability of a patient to transport of carotenoids from the gut into the serum will also be diagnostic of that person's ability to similarly transport cholesterol. Since mutations in ABC1 are a major cause of FHA, the carotenoid absorption test might constitute a clinically useful diagnostic procedure for identifying patients with ABC1 mutations and thus categorize patients for subsequent therapy. Continue reading... Full patent description for Cholesterol transport gene Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Cholesterol transport gene patent application. 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