US2002094956A1PendingUtilityA1
Use of alpha1beta1 integrin receptor inhibitors and TGF-beta1 inhibitors in the treatment of kidney disease
Assignee: BOYS TOWN NAT RES HOSPITALPriority: May 22, 1998Filed: Mar 12, 2002Published: Jul 18, 2002
Est. expiryMay 22, 2018(expired)· nominal 20-yr term from priority
Inventors:Dominic Cosgrove
A61P 43/00A61K 31/4745A61P 13/12A61K 31/436A61K 2039/505C09K 3/18C07K 2317/76A61K 38/39C07K 16/2842Y10S977/907
41
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Claims
Abstract
The present invention provides methods for treating (i.e., delaying the onset of, slowing the progression of, and/or reversing) kidney disorders (e.g., renal glomerulonephritis and/or renal fibrosis). Certain of these methods involve administering an α1β1 integrin receptor inhibitor optionally in combination with a TGF-β1 inhibitor. The present invention also provides a mouse model for kidney disease wherein the mouse does not express a normal collagen type 4 composition in the GBM (i.e., it does not incorporate collagen α3(IV), α4(IV), and α5(IV) chains into its glomerular basement membrane) and does not express the α1β1 integrin receptor.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of limiting a kidney disorder in a patient comprising administering to the patient an effective amount of an α1β1 integrin receptor inhibitor.
2 . The method of claim 1 further comprising administering to the patient an affective amount of a TGF-β1 inhibitor.
3 . The method of claim 2 wherein the α1β1 integrin receptor inhibitor and the TGF-β1 inhibitor are administered simultaneously.
4 . The method of claim 2 wherein the TGF-β1 inhibitor irreversibly binds to TGF-β1 and inhibits its ability to bind with its receptor.
5 . The method of claim 2 wherein the TGF-β1 inhibitor is an agent that inhibits the ability of TGF-β1 to transduce signals to the nucleus of a kidney cell.
6 . The method of claim 5 wherein the TGF-β1 inhibitor is a calcineurin inhibitor.
7 . The method of claim 6 wherein the calcineurin inhibitor is tacrolimus.
8 . The method of claim 1 wherein the α1β1 integrin receptor inhibitor is a blocking agent that binds to the α1β1 integrin receptor binding site on the surface of a kidney cell.
9 . The method of claim 8 wherein the α1β1 integrin receptor blocking agent comprises a peptide.
10 . The method of claim 9 wherein the peptide is at least a 9-mer fragment of a protein selected from the group consisting of laminin, fibronectin, entactin, and collagen type 4.
11 . The method of claim 8 wherein the peptide is an antibody.
12 . The method of claim 1 wherein the kidney disorder comprises renal glomerulonephritis, renal fibrosis, or both.
13 . The method of claim 12 wherein the renal glomerulonephritis or renal fibrosis is associated with Alport syndrome, IDDM nephritis, mesangial proliferative glomerulonephritis, membrano proliferative glomerulonephritis, crescentic glomerulonephritis, diabetic nephropathy, and renal insterstitial fibrosis.
14 . A method of delaying the onset of and/or slowing the progression of Alport syndrome in a patient, the method comprising administering to the patient an effective amount of an agent that inhibits signal transduction through an α1β1 integrin receptor of a kidney cell.
15 . A method of delaying the onset of and/or slowing the progression of Alport syndrome in a patient, the method comprising blocking an α1β1 integrin receptor binding site on the surface of a kidney cell of the patient.
16 . The method of claim 15 wherein blocking the α1β1 integrin receptor binding site comprises contacting the kidney cell with an effective amount of an α1β1 integrin receptor binding site peptide.
17 . The method of claim 16 wherein the peptide is at least a 9-mer fragment of a protein selected from the group consisting of laminin, fibronectin, entactin, and collagen type 4.
18 . The method of claim 15 further comprising administering to the patient an effective amount of a TGF-β1 inhibitor.
19 . The method of claim 18 wherein the TGF-β1 inhibitor irreversibly binds to TGF-β1 and inhibits its ability to bind with its receptor.
20 . The method of claim 18 wherein the TGF-β1 inhibitor is an agent that inhibits the ability of TGF-β1 to transduce signals to the nucleus of a kidney cell.
21 . The method of claim 20 wherein the TGF-β1 inhibitor is a calcineurin inhibitor.
22 . The method of claim 21 wherein the calcineurin inhibitor is tacrolimus.
23 . A method for delaying the onset of and/or slowing the progression of kidney disease in insulin dependent diabetes mellitus in a patient, the method comprising administering to the patient an effective amount of an agent that inhibits signal transduction through an α1β1 integrin receptor of a kidney cell.
24 . A method for delaying the onset of and/or slowing the progression of kidney disease in insulin dependent diabetes mellitus in a patient, the method comprising blocking an α1β1 integrin receptor binding site on the surface of a kidney cell of the patient.
25 . A method of limiting renal fibrosis in a patient, the method comprising reducing TGF-β1 activity in the patient while inhibiting α1β1 integrin receptors of the patient's kidney cells.
26 . The method of claim 25 wherein the step of reducing TGF-β1 activity comprises administering to the patient an agent that irreversibly binds to TGF-β1 and inhibits its ability to bind with its receptor.
27 . The method of claim 26 wherein the step of reducing TGF-β1 activity comprises administering to the patient an agent capable of inhibiting the ability of TGF-β1 to transduce signals to the nucleus of a kidney cell.
28 . A method of limiting renal fibrosis in a patient comprising administering to the patient a calcineurin inhibitor.
29 . The method of claim 28 wherein the calcineurin inhibitor is tacrolimus.
30 . A mouse model for kidney disease wherein the mouse does not express a normal collagen type 4 composition in the glomerular basement membrane of the mouse and does not express the α1β1 integrin receptor.
31 . The mouse model of claim 30 wherein the mouse does not incorporate collagen α3(IV), α4(IV), and α5(IV) chains into its glomerular basement membrane.
32 . A method of screening an agent for use in limiting a kidney disorder, comprising administering the agent to a mouse model for kidney disease, wherein the mouse does not express a normal collagen type 4 composition in the glomerular basement membrane of the mouse and does not express the α1β1 integrin receptor.
33 . A method of limiting matrix accumulation in the GBM of a patient with Alport Syndrome comprising reducing TGF-β1 activity in the patient.
34 . A method of delaying the onset of and/or slowing the progression of kidney disease in a patient, the method comprising administering to the patient an effective amount of an α1β1 integrin receptor inhibitor.
35 . The method of claim 34 wherein the α1β1 integrin receptor inhibitor comprises a peptide.
36 . The method of claim 35 wherein the peptide is an antibody.
37 . The method of claim 34 further comprising administering to the patient an effective amount of a TGF-β1 inhibitor.
38 . The method of claim 37 wherein the TGF-β1 inhibitor is a calcineurin inhibitor.
39 . The method of claim 38 wherein the calcineurin inhibitor is tacrolimus.
40 . The method of claim 34 wherein the α1β1 integrin receptor inhibitor and the TGF-β1 inhibitor are administered simultaneously.
41 . The method of claim 37 wherein the TGF-β1 inhibitor is a chimeric murine fusion protein.
42 . The method of claim 41 wherein the TGF-β1 inhibitor is a chimeric murine fusion protein.Join the waitlist — get patent alerts
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