Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Hormones – e.g. – prolactin – thymosin – growth factors – etc.
Reexamination Certificate
2001-04-23
2003-05-06
Carlson, Karen Cochrane (Department: 1653)
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Hormones, e.g., prolactin, thymosin, growth factors, etc.
C530S324000, C514S002600, C514S012200, C514S805000, C930S120000, C435S069400
Reexamination Certificate
active
06559289
ABSTRACT:
BRIEF DESCRIPTION OF THE INVENTION
The present invention relates to the use of biologically active compounds selected from GH, analogues thereof and GH-releasing compounds, as lipid lowering agents for the preparation of a drug for the treatment of mammals with homozygous familial hypercholesterolemia. By the furnishing of a drug comprising compounds selected from GH, analogues thereof and GH-releasing compounds, optionally in combination with further lipid lowering treatment, elevated plasma cholesterol in LDLR deficient mammals with familial hypercholesterolemia of the homozygous form may be treated.
Growth hormone (GH) has pleiotropic effects on cholesterol metabolism. GH stimulates the expression of hepatic low density lipoprotein (LDL)-receptors and the activity of cholesterol 7&agr;-hydroxylase (C7&agr;OH), a key regulatory step in bile acid synthesis. According to the present invention it is shown that GH treatment reduces plasma cholesterol in the situation of homozygous familial hypercholesterolemia as represented by the recently developed LDL-receptor knockout mouse strain.
GH infusion into LDL-receptor knockout mice resulted in a 30-40% reduced plasma cholesterol level. In addition, the reduced enzymatic activities of cholesterol 7&agr;-hydroxylase and HMG CoA reductase were normalized. It is concluded that GH treatment reduces the severe homozygous form of familial hypercholesterolemia in LDLR-deficient mice. Such therapy gives a beneficial effect in the heavily therapy resistant disease homozygous familial hypercholesterolemia, a disorder known to be strongly resistant to lipid-lowering treatment.
In this specification and the appended claims the following abbreviations are used: C7&agr;OH, represents cholesterol 7&agr; hydroxylase; HMG CoA reductase, represents 3-hydroxy-3-methyl-glutaryl coenzyme A reductase; FPLC, represents fast performance liquid chromatography; GH, represents growth hormone; HDL, represents high density lipoprotein; LDL, represents low density lipoprotein; LDLR, represents low density lipoprotein receptor; LDLRKO, represents low density lipoprotein receptor knockout; SDS-PAGE, represents sodium dodecyl sulphate-polyacrylamide gel electrophoresis; TNA, represents total nucleic acid; VLDL, represents very low density lipoprotein.
BACKGROUND OF THE INVENTION
Familial hypercholesterolemia (FH) is a common autosomal dominant inherited disease and is present in heterozygous and homozygous forms.
Heterozygous FH occurs at a frequency of approx. 1:300-500 in the general population. The subjects have type II-A lipid pattern and approximately twice the normal low-density lipoprotein (LDL) cholesterol levels. Heterozygotes have an increased risk to develop premature heart disease and their expected life span is reduced 10 to 15 years. FH heterozygotes have a mutation in the gene encoding the LDL receptor. This receptor is located on the surface of cells in the liver and other organs. The LDL receptors bind LDL and facilitate its uptake by receptor-mediated endocytosis and subsequent delivery to lysosomes, where the LDL is degraded yielding free cholesterol for cellular use. When LDL receptors are deficient, the rate of removal of LDL from plasma declines, and the level of LDL rises in inverse proportions to the receptor number. The excess plasma LDL is deposited in scavenger cells and other cell types, producing atheromas and xanthomas. FH heterozygotes have one normal and one mutant allele at the LDL receptor locus; hence their cells are able to bind and degrade LDL at approximately half the normal rate. (See In: The metabolic and molecular bases of inherited disease. Seventh edition, Mac Graw-Hill, Chapter 62, Familial Hypercholesterolemia, by J. L. Goldstein et al., pp 1981-2030).
Subjects with the homozygous form of FH (incidence=1:10
6
) have plasma cholesterol levels 3-5 fold higher than normal subjects and frequently develop coronary heart disease in childhood, almost invariably before 20 years of age. Homozygotes possess two mutant alleles at the LDL receptor locus, and their cells show a total or near total inability to bind or take up LDL.
There are two animal models for FH that closely resemble the human disease. The first is a natural mutant strain of rabbits, Watanabe Heritable Hyperlipidemic (WHHL) rabbits, and the second is the recently available mouse LDLR knock-out (LDLRKO) strain developed by Herz et al (Ishibashi, S. et al. 1993. J. Clin. Invest. 92; 883-893). Previous studies in WHHL-rabbits have shown that homozygous animals have strongly suppressed activity of the regulatory enzyme C7&agr;OH (Xu et al. 1995. J. Clin. Invest. 95; 1447-1504).
In the therapy of type II-A hyperlipidemia, the strategy is based on the concept of increasing the number of available hepatic LDL-receptors which in turn will reduce plasma cholesterol due to an increased hepatic uptake of LDL and LDL precursor lipoproteins, such as intermediate density lipoprotein, (IDL). In heterozygous FH, the most effective therapy is by interfering with the enterohepatic circulation of bile acids by orally administered bile acid sequestrants such as cholestyramine in combination with specific 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase inhibitors. An increasing number of such drugs (statins and vastatins) have been introduced to the market. Such combined therapy can reduce, but does seldom completely normalize plasma LDL.
However, in homozygotes that do not harbor any functional LDL receptors, other means to reduce the high LDL levels must be employed. This disease type is a candidate for gene therapy. Such treatment has been tested in laboratory animals using the LDLR gene and the gene encoding cholesterol 7&agr;-hydroxylase (C7&agr;OH), the key regulatory step in the synthesis of bile acids. (Ishibashi, S. et al. 1993. J. Clin. Invest. 92, 883-893, Spady, D. K. and Cuthbert, J. A. 1995. J. Clin. Invest 96; 700-709). The effects are unfortunately transient. So far, the only available therapy has been liver transplantation or plasmapheresis and/or selective extracorporeal removal of cholesterol-rich LDL-particles. The latter therapy, if performed every 2-3 weeks, can reduce but not normalize the increased plasma cholesterol level. Recently it has been shown that certain FH homozygotes can also benefit from high dose statin therapy (Marais, A. D et al. 1997. J. Lipid Res. 38:2071-8). Therefore, until gene-therapy will be clinically available, there is a need of novel pharmacological therapeutic strategies in homozygous FH.
Pituitary growth hormone (GH) has several effects on cholesterol and lipid metabolism. We have previously shown that GH therapy has a stimulatory effect on the hepatic LDLR expression in both rats and humans (Rudling, M. et al. Proc. Natl. Acad. Sci. USA. 1992, 89; 6983-6987), and in particular we have identified GH as an important stimulator of the enzymatic activity of C7&agr;OH (Rudling et al, 1997, J. Clin. Invest. 99; 2239-2245). We have shown that GH stimulates C7&agr;OH activity, not only in hypophysectomized animals, but also in normal young rats (P. Parini, et al. 1999, Cholesterol and lipoprotein metabolism in aging: reversal of hypercholesterolemia by growth hormone treatment in old rats, Arterioscl. Thromb. & Vasc. Biol. 19;832-839). The experiments were performed in mammals expressing normal LDL receptors.
From “Current opinion in Lipidology”, 1997,Vol. 8, p. 337-341 by B. Angelin as well as from “Metabolism”, 1996, Vol. 45 No. 11, p. 1414-1421 by Tostad et al. it was evident that familial hypercholesterolemia of the heterozygous form may benefit from treatment with GH because such patients express functional LDL receptors.
However, because homozygotes do not harbor functional LDL receptors, it was not for a man skilled in the art obvious that the homozygous form of the disease may benefit from GH treatment.
DESCRIPTION OF THE INVENTION
We have now surprisingly found that administration of compounds selected from GH, analogues thereof and GH-releasing compounds, optionally in combination with established lipid-lowering
Angelin Bo
Rudling Mats
Burns, Doane, Swecker & Swecker & Mathis, L.L.P.
Carlson Karen Cochrane
Kam Chih-Min
Salhtech I Goteborg AB
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