Hip/pap polypeptide compositions for use in liver regeneration and for the prevention of liver failure

Abstract

This invention is based on the experimental finding that HIP/PAP has mitogenic and antiapoptotic effects in vitro on hepatocytes in primary culture. Moreover, HIP/PAP is a mitogenic and anti-apoptotic molecule for hepatocytes, in vivo, during liver failure and liver regeneration. The present invention is also based on the experimental finding that HIP/PAP administration has no adverse effects in mammals. This invention concerns a pharmaceutical composition for stimulating liver regeneration in vivo including after chronic/acute liver failure, comprising an effective amount of a polypeptide comprising an amino acid sequence having 90% amino acid identity with the polypeptide consisting of the amino acid sequence starting at the amino acid residue (36) and ending at the amino acid residue (175) of sequence SEQ ID No. 1, in combination with at least one physiologically acceptable excipient.

1 - 17 . (canceled)  
     
     
         18 . A pharmaceutical composition comprising a polypeptide comprising an amino acid sequence having at least 90% amino acid identity with the amino acid sequence from amino acid residue 36 to amino acid residue 175 of SEQ ID NO: 1 and at least one physiologically acceptable excipient.  
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein the polypeptide is further defined as comprising an the amino acid sequence from amino acid residue 36 to amino acid residue 175 of SEQ ID NO: 1.  
     
     
         20 . The pharmaceutical composition of  claim 18 , wherein the polypeptide is further defined as comprising an amino acid sequence having 90% amino acid identity with the amino acid sequence from amino acid residue 27 to amino acid residue 175 of SEQ ID NO:1.  
     
     
         21 . The pharmaceutical composition of  claim 18 , wherein the polypeptide is further defined as comprising the amino acid sequence from amino acid residue 27 to amino acid residue 175 of SEQ ID NO: 1.  
     
     
         22 . The pharmaceutical composition of  claim 18 , wherein the polypeptide is further defined as a human hepatocarcinoma-intestine-pancreas/pancreatic-associated protein (HIP/PAP) with the amino acid sequence of SEQ ID NO: 1.  
     
     
         23 . The pharmaceutical composition of  claim 18 , wherein the polypeptide is comprised in an amount effective to stimulate liver regeneration in vivo.  
     
     
         24 . The pharmaceutical composition of  claim 23 , wherein the polypeptide is comprised in an amount effective to stimulate liver regeneration after chronic or acute liver failure.  
     
     
         25 . The pharmaceutical composition of  claim 18 , further defined as comprising a therapeutically effective amount of a hepatotoxic compound.  
     
     
         26 . The pharmaceutical composition of  claim 25 , further defined as resulting in limited liver necrosis during use.  
     
     
         27 . A method of treating a subject comprising: 
 obtaining a pharmaceutical composition of  claim 18;  and    administering the pharmaceutical composition to a subject.    
     
     
         28 . The method of  claim 27 , wherein the subject is a human.  
     
     
         29 . The method of  claim 27 , further defined as a method of stimulating liver regeneration in the subject.  
     
     
         30 . The method of  claim 27 , wherein the subject has chronic or acute liver failure.  
     
     
         31 . The method of  claim 27 , wherein the subject is at risk of or has liver necrosis.  
     
     
         32 . The method of  claim 27 , wherein the subject has had a liver resection.  
     
     
         33 . The method of  claim 27 , wherein the subject has a partial liver transplant, a hepatic failure, hepatic cirrhosis, or hepatic cancer.  
     
     
         34 . The method of  claim 33 , wherein the subject has hepatic failure caused by liver disease.  
     
     
         35 . The method of  claim 33 , wherein the subject has hepatic cirrhosis of alcoholic, viral, or drug cause.  
     
     
         36 . The method of  claim 27 , wherein the subject has Hepatitis B, Hepatitis C, Urea Cycle defects, Familial hypercholesterolemia, Alcohol induced cirrhosis, Glycogen Storage Disease, Autoimmune Hepatitis, Primary Hyperoxaluria type 1, Cryptogenic cirrhosis, Crigler-Najjar syndrome type 1, Congenital Hepatic Fibrosis, Neimann-Pick Disease, Primary Biliary Cirrhosis, Familial Amyloidosis, Biliary Atresia, Hepatocellular Carcinoma, Primary Sclerosing Cholangitis, Hepatoblastoma, Alagille Syndrome, Hemangioendothelioma, Familial Cholestasis, Non-Carciniod neuro-endocrine, Drug induced liver failure, benign liver tumor, liver tumor, Acute and or fulminant liver failure, Budd-Chiari syndrome, Alpha-1-antitrypsin deficiency, Wilson Disease, Hemochromatosis, Tyrosinemia, Protoporphyria, and/or Cystic fibrosis.  
     
     
         37 . A composition comprising a polypeptide comprising an amino acid sequence having at least 90% amino acid identity with the amino acid sequence from amino acid residue 36 to amino acid residue 175 of SEQ ID NO:1 and a cell.  
     
     
         38 . The composition of  claim 37 , wherein the cell is a hepatocyte.  
     
     
         39 . The composition of  claim 38 , wherein the hepatocyte is a dividing hepatocyte.  
     
     
         40 . The composition of  claim 37 , wherein the cell is a bone-marrow stem cell.  
     
     
         41 . A cell comprising an expression cassette that drives expression of a polypeptide comprising an amino acid sequence having at least 90% amino acid identity with the amino acid sequence from amino acid residue 36 to amino acid residue 175 of SEQ ID NO:1.  
     
     
         42 . The cell of  claim 41 , further defined as a hepatocyte.  
     
     
         43 . A pharmaceutical composition comprising: 
 a polypeptide comprising an amino acid sequence having at least 90% amino acid identity with the amino acid sequence from amino acid residue 36 to amino acid residue 175 of SEQ ID NO:1 and a cell; or    a cell comprising an expression cassette that drives expression of a polypeptide comprising an amino acid sequence having at least 90% amino acid identity with the amino acid sequence from amino acid residue 36 to amino acid residue 175 of SEQ ID NO: 1.    
     
     
         44 . A process for stimulating cell growth in vitro comprising: 
 (a) collecting cells;    (b) cultivating said cells in an appropriate culture medium; and    (c) treating said cells with a mitogenic amount of a polypeptide comprising an amino acid sequence having at least 90% amino acid identity with the amino acid sequence from amino acid residue 36 to amino acid residue 175 of SEQ ID NO: 1; or transfecting the cell with an expression cassette that drives expression of a polypeptide comprising an amino acid sequence having at least 90% amino acid identity with the amino acid sequence from amino acid residue 36 to amino acid residue 175 of SEQ ID NO: 1.    
     
     
         45 . The process of  claim 44 , further defined as a process for stimulating hepatocyte growth in vitro comprising: 
 (a) collecting hepatocytes;    (b) cultivating said hepatocytes in an appropriate culture medium; and    (c) treating said hepatocytes with a mitogenic amount of a polypeptide comprising an amino acid sequence having at least 90% amino acid identity with the amino acid sequence from amino acid residue 36 to amino acid residue 175 of SEQ ID NO: 1.    
     
     
         46 . The process of  claim 44 , further defined as a process for stimulating hepatocyte growth in vitro comprising: 
 (a) collecting hepatocytes;    (b) cultivating said hepatocytes in an appropriate culture medium; and    (c) transfecting said hepatocytes with an expression cassette that drives expression of a polypeptide comprising an amino acid sequence having at least 90% amino acid identity with the amino acid sequence from amino acid residue 36 to amino acid residue 175 of SEQ ID NO: 1.    
     
     
         47 . The process of  claim 44 , further defined as a process for treating bone marrow-stem cells in vitro comprising: 
 (a) collecting bone marrow stem cells;    (b) cultivating said bone marrow stem cells in an appropriate culture medium; and    (c) treating said bone marrow stem cells with a mitogenic amount of a polypeptide comprising an amino acid sequence having at least 90% amino acid identity with the amino acid sequence from amino acid residue 36 to amino acid residue 175 of SEQ ID NO: 1.    
     
     
         48 . The process of  claim 44 , further defined as a process of manufacturing a pharmaceutical composition.