Patent EA-004145-B1 (EA)
Title: USE OF alpha1beta1 INTEGRIN RECEPTOR INHIBITORS AND TGF-beta1 INHIBITORS IN THE TREATMENT OF KIDNEY DISEASE
Inventor: COSGROVE DOMINIC
IPC: C09K3/18
Filed: 1999-05-19
Abstract: 1. A method of treating or limiting a kidney disorder in a patient comprising administering to the patient an effective amount of alpha1beta1 integrin receptor inhibitor. 2. The method of claim 1, wherein the kidney disorder comprises renal glomerulonephritis, renal fibrosis, or both. 3. The method of claim 2, 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 interstitial fibrosis. 4. The method of any of claims 1-3, wherein the alpha1beta1 integrin receptor inhibitor is a blocking agent that binds to the alpha1beta1 integrin receptor binding site on the surface of a kidney cell. 5. A method of delaying the onset of and/or slowing the progression of Alport syndrome in a patient, the method comprising blocking an alpha1beta1 integrin receptor binding site on the surface of a kidney cell of the patient. 6. 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 alpha1beta1 integrin receptor binding site on the surface of a kidney cell of the patient. 7. The method of claims 4-6, wherein blocking of the alpha1beta1 integrin receptor binding site comprises an agent which contain peptide with antibody against this peptide or proteolytic fragment. 8. The method of claim 7, wherein the peptide is an antibody. 9. The method of claim 8, 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. 10. 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 alpha1beta1 integrin receptor of a kidney cell. 11. 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 inhibitor of an alpha1beta1 integrin receptor. 12. A method of treating roughnesses of a glomerular basement membrane in a patient comprising administering to the patient an effective amount of an inhibitor of an alpha1beta1 integrin receptor. 13. A method of claim 12, wherein roughnesses of the glomerular basement membrane cause effacement of the podocyte foot processes. 14. The method of claims 10, 11 or 12, wherein the alpha1beta1 integrin receptor inhibitor comprises a peptide. 15. The method of claim 14, wherein the peptide is an antibody. 16. The method of any one claims 5-9 further comprising administering to the patient an TGF-beta1 inhibitor. 17. The method of any one claims 1-4 or 10-12 further comprising administering to the patient an TGF-beta1 inhibitor. 18. The method of claim 2 wherein the alpha1beta1 integrin receptor inhibitor and the TGF-beta1 inhibitor are administered simultaneously or in sequence. 19. The method of claim 16, 17 or 18 wherein the TGF-beta1 inhibitor irreversibly binds to TGF-beta1 and inhibits its ability to bind with its receptor. 20. The method of claim 16, 17 or 18 wherein the TGF-beta1 inhibitor is an agent that inhibits the ability of TGF-beta1 to transduce signals to the nucleus of a kidney cell. 21. The method of claim 20 wherein the TGF-beta1 inhibitor is a calcineurin inhibitor or chimeric compact protein. 22. 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 alpha1beta1 integrin receptor of a kidney cell. 23. A method of limiting rental fibrosis in a patient comprising reducing TGF-beta1 activity in the patient while simultaneously inhibiting alpha1beta1 integrin receptors of the patient's kidney cells. 24. The method of claim 23 wherein the step of reducing TGF-beta1 activity comprises administering to the patient an agent that irreversibly binds to TGF-beta1 and inhibits its ability of TGF-beta1 to transduce signals to the nucleus of a kidney cell. 25. A method of limiting rental fibrosis in a patient comprising administering an effective amount of calcineurin inhibitor. 26. The method of claim 21 or 25 wherein the calcineurin inhibitor is tacrolimus. 27. 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 alpha1 integrin receptor. 28. The mouse model of claim 27 wherein the mouse does not incorporate collagen alpha3 (IV), alpha4 (IV), and alpha5 (IV) chains into its glomerular basement membrane. 29. A method of screening an agent for use in limiting a kidney disorder, comprising administering the agent to a mouse model of claim 27 or 28 and further evaluation of kidney tissue of said model. 30. A method of limiting matrix accumulation in the GBM of a patient with Alport Syndrome comprising reducing TGF-beta1 activity in the patient. 31. A pharmaceutical composition comprising a alpha1beta1 integrin receptor inhibitor and an TGF-beta1 inhibitor. 32. The pharmaceutical composition of claim 31 wherein the alpha1beta1 integrin receptor inhibitor is a blocking agent binds to the alpha1 integrin receptor binding site on the surface of a kidney cell. 33. The pharmaceutical composition of claim 32 wherein said agent blocking the alpha1beta1 integrin receptor comprises peptide neutralizing an antibody or proteolytic fragment. 34. The pharmaceutical composition of claim 33 wherein said peptide is at least a 9-mer fragment of a protein selected from the group consisting of laminin, fibronectin, entactin and collagen type 4. 35. The pharmaceutical composition of any one of claims 31-34 wherein the TGF-beta1 inhibitor irreversibly binds to the TGF-beta1 and inhibits its ability to bind with its receptor. 36. The pharmaceutical composition of any one of claims 31-34 wherein the TGF-beta1 is an agent capable of inhibiting the ability of the TGF-beta1 to transduce signals to the nucleus of a kidney cell. 37. The pharmaceutical composition of claim 36 wherein the TGF-beta1 is a calcineurin inhibitor. 38. The pharmaceutical composition of claim 37 wherein the calcineurin inhibitor is tacrolimus.