Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-04-15
2002-12-10
Borin, Michael (Department: 1631)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C424S130100
Reexamination Certificate
active
06492325
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the field of kidney disease (i.e., kidney disorder) characterized by glomerulonephritis and/or fibrosis. In particular, this invention relates to the use of &agr;1&bgr;1 integrin receptor inhibitors in kidney disorders. Further, this invention relates to the use of &agr;1&bgr;1 integrin inhibitors in combination with TGF-&bgr;1 inhibitors in kidney disorders.
BACKGROUND OF THE INVENTION
In the United States, approximately 12,000 people currently live with Alport syndrome. This inherited disorder results in progressive renal disease that is only treatable by dialysis and kidney transplant. Transplanted kidneys are usually rejected. Thus, alternative treatments are needed. However, there is currently no treatment that addresses the mechanism of the disease onset or progression. Thus, what is needed is a treatment method that attacks the mechanism of disease onset and/or progression, one that could substantially slow disease conditions, such as renal glomerulonephritis and renal fibrosis.
A number of kidney diseases are associated with alterations in matrix homeostasis, where the delicate balance of synthesis and turnover of structural molecules is interrupted. As one example, Alport syndrome is a disease resulting in progressive renal failure and is associated with sensorineural hearing loss. Male carriers are most affected and ultrastructural studies reveal abnormalities in the glomerular basement membrane (GBM) of affected individuals. About one in 20,000 people have Alport syndrome, making the disease one of the more prevalent known genetic disorders. See, for example, Atkin et al., “Alport Syndrome” In R. W. Schrier & C. W. Gottschalk (Eds.),
Diseases of the Kidney,
4th ed., Chap. 19, Little Brown, Boston, pp. 617-641, 1988. X-linked Alport syndrome is caused by any of a series of mutations in the collagen 4A5 gene (Barker et al.,
Science,
248:1224-1227, 1990). At least 60 different mutations in the gene have been identified. The autosomal form of Alport syndrome displays the same range of phenotypes as the X-linked form and results from mutations in either basement membrane collagen gene 4A3 (COL4A3) or 4A4 (COL4A4). See, for example, Lemmink et al.,
Hum. Mol. Gen.,
3:1269-1273, 1994, and Mochizuki et al.,
Nature Genet.,
8:77-81, 1994. Other diseases of the basement membrane include Goodpasture syndrome, which is due to an acute autoimmune response directed against an epitope on the NCl domain of collagen 4A3 (Hudson et al.,
Kidney Int.,
43:135-139, 1993), and diffuse leiomyomatosis, a benign smooth muscle tumor that is associated with a deletion of both collagen 4A5 and 4A6 (Zhou et al.,
Science,
261:1167-1169, 1993).
Basement membranes are specialized extracellular structures associated with nearly every organ and tissue in the body. They are usually found at the boundary between cells and connective tissue, but may also be found between epithelial and endothelial cells, as is the case in a kidney glomerulus (i.e., cluster of capillaries). The predominant building blocks of basement membranes include type IV collagen, laminin, heparin sulfate proteoglycan, entactin, and sometimes fibronectin and type V collagen. The most highly represented component in all basement membranes is type IV collagen, a distinct collagen type found only in basement membranes. In its native form, type IV, like all collagens, is composed of three collagen molecules assembled in a triple helix consisting of distinct combinations of the six alpha chains (4A1-4A6). The 4A1 and 4A2 chains (also referred to as the &agr;1(IV) and &agr;2(IV) chains) are the most common (Timp1,
Eur. J. Biochem.,
180:487-502, 1989). Type IV collagens differ from interstitial collagens in a number of ways. The helical structure of the alpha chain association does not strictly adhere to the glycine-X-Y motif observed in other collagens; it contains 3-hydroxyproline rather than 4-hydroxyproline, and is rich in carbohydrate. The resulting superstructure of collagen is a chicken wire-like network of basement membrane collagen. This network is the foundation onto which the accessory molecules (laminin, heparin sulfate, etc.) bind.
Basement membranes are very heterogeneous structures, which accounts for their diverse functional properties. The complexity of these structures is still poorly understood. Several novel basement membrane collagen chains (alpha 3, 4, 5, and 6 chains) were only recently discovered. See, for example, Gunwar et al.,
J. Biol. Chem.,
266:15318-15324, 1991; Hostikka et al.,
Proc. Natl. Acad. Sci. USA,
87:1606-1610, 1990; Butkowski et al.,
J. Biol. Chem.,
262:7874-7877, 1987; and Zhou et al.,
Science,
261:1167-1169, 1993. Interestingly, the novel chains have been found only in certain tissues (e.g., the glomerulus of the kidney, the Decimet's membrane of the eye, the lens, the skin, the lung, the testis, and the cochlea). See, for example, Kleppel et al.,
Am. J. Pathol.,
134:813-825, 1989, and Tryggvason et al.,
Kidney Int.,
43:38-44, 1993. The role of these novel chains in basement membrane assembly and function is currently unknown. It is believed that these novel basement membrane collagens form separate networks distinct from the networks of collagen types 4A1 (&agr;1(IV)) and 4A2 (&agr;2(IV)).
Kidney glomerular basement membranes (GBMs) are integral to the ultrafiltration process (i.e., in which blood is filtered to remove metabolites for excretion in the form of urine, for example). Alport syndrome results in a massive accumulation of extracellular matrix and a compromised basement membrane, resulting in focal and segmental glomerulonephritis (i.e., inflammation of the capillary loops in the glomeruli of the kidney), which ultimately results in fatal uremia (i.e., excess urea in the blood as a result of kidney failure). Many of the same extracellular matrix molecules (e.g., collagen type I, fibronectin, laminin, and collagen type IV) also progressively accumulate in the GBM of patients with IDDM (insulin dependent diabetes mellitus) nephritis. In this disease, however, the GBM thickens, but lacks the focal thinning and splitting (segmenting) of the GBM, which is characteristic of Alport syndrome.
The integrins are a family of heterodimeric transmembrane glycoprotein receptors that bind to components of basal lamina and extracellular matrix. They function as adhesion molecules involved in cell aggregation and in anchoring cells to basal lamina. They also transduce signals to the nucleus, and are involved in modulating gene expression, particularly gene expression for cell migration and cell differentiation (Hynes,
Cell,
69:11-25, 1992). Over 20 different integrin receptors are known, which include about 14 different alpha subunits and about 8 different beta subunits (DeSimone,
Curr. Opin. Cell Biol.,
6:747-751, 1994).
In the renal (kidney) glomerulus, there are distinct sets of integrin receptors. These are associated with either the mesangial matrix (i.e., a membrane that helps support the capillary loops in a kidney glomerulus) or visceral epithelial cells (Patey et al.,
Cell Adhesion Commun.,
2:159-167, 1994). The most prevalent integrin receptor on adult glomerular visceral epithelial cells is the &agr;3&bgr;1 heterodimer (Adler,
Am. J. Pathol.,
141:571-578, 1992; and Patey et al.,
Cell Adhesion Commun.,
2:159-167, 1994). The &bgr;5 subunit has been shown to be expressed in adult visceral epithelial cells (Yamada et al.,
Cell Adhesion Communic.,
3:311-325, 1995), and the &agr;1, &agr;3, &agr;5, &agr;V, &bgr;1, and &bgr;3 integrin receptors are expressed developmentally during kidney morphogenesis (Korhonen et al.,
Lab. Invest.,
62:616-625, 1990; Wada et al.,
J. Cell. Biol.,
132:1161-1176, 1996; and Yamada et al.,
Cell Adhesion Communic.,
3:311-325, 1995). The &agr;1&bgr;1 heterodimeric integrin receptor is the only integrin receptor identified on the surface of mesangial cells in the renal glomerulus.
A gene knockout mouse at the &agr;3 integrin receptor subunit has been produced. The offspring die of
Borin Michael
Boys Town National Research Hospital
Mueting Raasch & Gebhardt, P.A.
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