Composition Comprising and Method of Using Angiopoietin-Like Protein 3 ANGPTL3

Abstract

The present invention is directed to methods and means for making and using Angpt13 polypeptides. The invention specifically concerns the use of Angpt13 polypeptides in inducing liver regeneration and angiogenesis. Further methods include the use of Angpt13 polypeptides in the diagnosis and treatment of liver disease. Also provided herein are antibodies which bind to the polypeptides of the present invention.

1 - 44 . (canceled)  
     
     
         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 Angpt13 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 Angpt13 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 (P1, SEQ ID NO: 14), 442-460 (P2, SEQ ID NOO: 15), and 415-430 (P3 SEQ ID NO: 17) of the human Angpt13 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 NOO: 15), and 415-430 (P3 SEQ ID NO: 17) of the human Angpt13 sequence of SEQ ID NO: 2.  
     
     
         50 . The method of  claim 46  wherein said polypeptide comprises the fibrinogen domain of the human Angpt13 sequence of SEQ ID NO: 2.  
     
     
         51 . The method of 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 Angpt13.  
     
     
         55 . The method of  claim 46  wherein said agonist is an agonist antibody specifically binding αv 3.  
     
     
         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 Angpt13 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 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 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 amino acid sequence having at least 80% sequence identity to the human Angpt13 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  is 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 of inhibiting an undesired increase in vascular permeability in a tissue comprising treating the tissue with an effective amount of an antagonist of Angpt13.  
     
     
         68 . The method of  claim 67  wherein the increase in vascular permeability of a 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 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 Angpt13 mRNA or its expression product in the heart tissue of said subject, relative to the level of Angpt13 or its expression product in normal heart tissue, and identifying the subject as being at risk if the level of Angpt13 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 Angpt13 mRNA or its expression product in the liver tissue of said subject, relative to the level of Angpt13 or its expression product in normal liver tissue, and identifying the subject as being at risk if the level of Angpt13 mRNA or its expression product in the liver tissue of the subject is elevated relative to the normal liver tissue.