Claims
- 1. A method of treating tissue damage characterized by overexpression of Angptl3, comprising treating the tissue with an antagonist of Angptl3.
- 2. The method of claim 1 wherein the tissue is human tissue, and the antagonist used is an antagonist of Angptl3 of SEQ ID NO: 2.
- 3. The method of claim 2 wherein the tissue is liver tissue.
- 4. The method of claim 3 wherein the tissue damage is associated with inflammation.
- 5. The method of claim 4 wherein the inflammation is associated with a chronic liver disease.
- 6. The method of claim 5 wherein the chronic liver disease is selected from the group consisting of liver cirrhosis, liver fibrosis, chronic hepatitis, viral hepatitis A, B, C, D, E and G, toxic metabolic liver damage, fatty liver, ischemia reperfusion injury of the liver, and sepsis.
- 7. The method of claim 6 wherein the liver cirrhosis is alcoholic liver cirrhosis or primary biliary cirrhosis (PBC).
- 8. The method of claim 6 wherein the hepatitis is selected from the group consisting of chronic autoimmune hepatitis, chronic alcoholic hepatitis, and non-alcoholic steatohepatitis (NASH).
- 9. The method of claim 3 wherein the tissue damage is associated with a liver tumor.
- 10. The method of claim 9 wherein the liver tumor is selected from the group consisting of hepatocellular carcinoma, cholangiocarcinoma, and metastatic cancer of the liver.
- 11. The method of claim 2 wherein the tissue is heart tissue.
- 12. The method of claim 11 wherein the tissue damage is associated with inflammation.
- 13. The method of claim 12 wherein the tissue damage is associated with a cardiac disease the pathogenesis of which includes an inflammatory response, or in the development of which inflammation is a risk factor.
- 14. The method of claim 11 wherein the tissue damage is associated with a cardiac disease characterized by elevated expression of Angptl3.
- 15. The method of claim 13 or claim 14 wherein the cardiac disease is selected from the group consisting of coronary artery disease, cardiomyopathy, myocarditis, congestive heart failure (CHF), and myocardial infarction.
- 16. The method of claim 15 wherein the cardiomyopathy is selected from the group consisting of non-specific hypertrophy and dilated cardiomyopathy.
- 17. The method of claim 2 wherein the treatment is prevention.
- 18. The method of claim 2 wherein the treatment involves prevention of the progression of tissue damage.
- 19. The method of claim 2 wherein the antagonist is an anti-Angptl3 antibody or an anti-αcβ3 antibody.
- 20. The method of claim 19 wherein the antibody is a monoclonal antibody.
- 21. The method of claim 20 wherein the antibody is an antibody fragment.
- 22. The method of claim 21 wherein the antibody fragment is selected from the group consisting of Fab, Fab′, F(ab′)2, and Fv fragments.
- 23. The method of claim 20 wherein the antibody is a single-chain antibody.
- 24. The method of claim 20 wherein the monoeclonal antibody is chimeric.
- 25. The method of claim 20 wherein the monoclonal antibody is humanized.
- 26. The method of claim 20 wherein the monoclonal antibody is human.
- 27. The method of claim 2 wherein the antagonist is an immunoadhesin.
- 28. The method of claim 27 wherein the immunoadhesin comprises at least the ligand-binding region of αvβ3 fused to an immunoglobulin sequence.
- 29. The method of claim 27 wherein the immunoadhesin comprises at least the receptor-binding region of Angptl3 used to an immunoglobulin sequence.
- 30. The method of claim 2 wherein the antagonist is a small molecule.
- 31. A method for the treatment of a chronic liver disease in a mammalian subject, comprising administering to a mammalian subject in need an effective amount of an antagonist of Angptl3.
- 32. The method of claim 31 wherein the mammalian subject is human.
- 33. The method of claim 32 wherein the antagonist administered is an antagonist of Angptl3 of SEQ ID NO: 2.
- 34. The method of claim 33 wherein the chronic liver is characterized by the elevated expression of Angptl3.
- 35. The method of claim 34 wherein the liver disease is selected from the group consisting of liver cirrhosis, liver fibrosis, chronic hepatitis, viral hepatitis A, B, C, D, E and G, toxic metabolic liver damage, fatty liver, ischemia reperfusion injury of the liver, and sepsis.
- 36. The method of claim 31 wherein the antagonist is an antibody.
- 37. The method of claim 36 wherein the antibody is an anti-Angptl3 antibody.
- 38. The method of claim 36 wherein the antibody is an anti-αvβ3 antibody.
- 39. A method for the treatment of a heart disease characterized by the elevated expression of Angptl3 in a mammalian subject, comprising administering to the subject an effective amount of an antagonist of Angptl3.
- 40. The method of claim 39 wherein the mammalian subject is human.
- 41. The method of claim 40 wherein the antagonist administered is an antagonist of Angptl3 of SEQ ID NO: 2.
- 42. The method of claim 41 wherein the heart disease is selected from the group consisting of coronary artery disease, cardiomyopathy, myocarditis, congestive heart failure (CHF), and myocardial infarction.
- 43. The method of claim 41 wherein the antagonist is an anti-Angptl3 antibody.
- 44. The method of claim 41 wherein the antagonist is an anti-αvβ3 antibody.
- 45. A method for the treatment of acute liver disease, comprising administering to a mammalian subject in need a therapeutically effective amount of a polypeptide comprising an amino acid sequence having at least 80% sequence identity to the human Angptl3 sequence of SEQ ID NO: 2, or an agonist thereof.
- 46. The method of claim 45 wherein the mammalian subject is human.
- 47. The method of claim 46 wherein said polypeptide comprises an amino acid sequence having at least 98% identity to the human Angptl3 sequence of SEQ ID NO: 2, or an agonist thereof.
- 48. The method of claim 46 wherein said polypeptide comprises amino acid regions 281-293 (PI, SEQ ID NO: 14), 442-460 (P2, SEQ ID NO: 15), and 415-430 (P3, SEQ ID NO: 17) of the human Angptl3 sequence of SEQ ID NO: 2.
- 49. The method of claim 47 wherein said polypeptide comprises amino acid regions 281-293 (P1, SEQ ID NO: 14), 442-460 (P2, SEQ ID NO: 15), and 415-430 (P3, SEQ ID NO: 17) of the human Angptl3 sequence of SEQ ID NO: 2.
- 50. The method of claim 46 wherein said polypeptide comprises the fibrinogen domain of the human Angptl3 sequence of SEQ ID NO: 2.
- 51. The method of claim 46 further comprising the administration of an additional therapeutic agent.
- 52. The method of claim 51 wherein said additional therapeutic agent is an angiogenic factor.
- 53. The method of claim 52 wherein said angiogenic factor is vascular endothelial growth factor (VEGF) or fibroblast growth factor (FGF).
- 54. The method of claim 46 wherein said agonist is an agonist antibody specifically binding Angptl3.
- 55. The method of claim 46 wherein the agonist is an agonist antibody specifically binding αvβ3.
- 56. A method of inducing liver regeneration following acute liver injury, comprising administering to a mammalian subject in need a therapeutically effective amount of a polypeptide comprising an amino acid sequence having at least 80% sequence identity to the human Angptl3 sequence of SEQ ID NO: 2, or an agonist thereof.
- 57. A method of claim 56 wherein the mammalian subject is human.
- 58. The method of claim 57 wherein the human subject has been diagnosed with an inflammatory liver disease.
- 59. The method of claim 58 wherein the inflammatory liver disease is chronic, alcoholic or viral hepatitis.
- 60. The method of claim 57 wherein the human subject has suffered chemical or mechanical injury to the liver.
- 61. The method of claim 57 wherein the human subject has been subject to hepatectomy.
- 62. The method of claim 61 wherein the hepatectomy is due to chronic hepatitis, liver cirrhosis, primary or metastatic liver cancer, or gallbladder cancer.
- 63. A method for inducing angiogenesis in a tissue comprising treating the tissue with an effective amount of a polypeptide comprising an amino acid sequence having at least 80% sequence identity to the human Angptl3 sequence of SEQ ID NO: 2, or an agonist thereof.
- 64. The method of claim 63 wherein the tissue is liver tissue.
- 65. The method of claim 63 wherein the liver tissue has been injured as a result of an infectious or autoimmune process, mechanical or chemical injury, or cancer or metastatic cancer.
- 66. The method of claim 63 wherein the tissue is cardiac tissue.
- 67. A method for inhibiting an undesired increase in vascular permeability in a tissue comprising treating the tissue with an effective amount of an antagonist of Angptl3.
- 68. The method of claim 67 wherein the increase in vascular permeability is increased permeability of small vessels following tissue damage.
- 69. The method of claim 68 wherein the increased vascular permeability follows necrosis of vascular endothelium due to exposure to toxins.
- 70. The method of claim 68 wherein the increased vascular permeability is associated with inflammation.
- 71. The method of claim 70 wherein the increased vascular permeability is associated with chronic inflammation.
- 72. The method of claim 67 wherein the tissue is liver tissue.
- 73. The method of claim 67 wherein the tissue is heart tissue.
- 74. A method for identifying a human subject at risk of cardiovascular disease, comprising determining the level of Angptl3 mRNA or its expression product in the heart tissue of said subject, relative to the level of Angptl3 or its expression product in normal heart tissue, and identifying the subject as being at risk if the level of Angptl3 mRNA or its expression product in the heart tissue of the subject is elevated relative to the normal heart tissue.
- 75. A method for identifying a human subject at risk of liver damage, comprising determining the level of Angptl3 mRNA or its expression product in the liver tissue of said subject, relative to the level of Angptl3 or its expression product in normal liver tissue, and identifying the subject as being at risk if the level of Angptl3 mRNA or its expression product in the liver tissue of the subject is elevated relative to the normal liver tissue.
RELATED APPLICATIONS
[0001] This is a continuation in part application that claims priority under 35 U.S.C. §119(e) to U.S. provisional application No. 60/332,429, filed on Nov. 16, 2001.
Provisional Applications (1)
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Number |
Date |
Country |
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60332429 |
Nov 2001 |
US |