Sulfatases and methods of use thereof

Abstract

Novel sulfatases and polypeptides related thereto, as well as nucleic acid compositions encoding the same, are provided. The subject polypeptides and nucleic acid compositions find use in a variety of applications, including various diagnostic and therapeutic agent screening applications. Also provided are methods of inhibiting tumor-induced angiogenesis and methods of treating disease conditions associated therewith, particularly by administering an inhibitor of a subject sulfatase.

1 . An isolated polypeptide comprising a hydrophilic domain of a sulfatase polypeptide, wherein said polypeptide lacks glucosamine-6-sulfatase activity.  
     
     
         2 . The polypeptide according to  claim 1 , wherein said sulfatase is a human sulfatase.  
     
     
         3 . The polypeptide according to  claim 1 , wherein said polypeptide comprises a fragment of from about 20 amino acids to about 300 amino acids of amino acids 415 to 735 of SEQ ID NO:3 or amino acids 416 to about 715 of SEQ ID NO:6.  
     
     
         4 . A composition comprising the polypeptide of  claim 1;  and a pharmaceutically acceptable carrier.  
     
     
         5 . The composition of  claim 4 , wherein said composition is formulated for oral delivery.  
     
     
         6 . The composition of  claim 5 , wherein said composition is formulated for delivery by injection.  
     
     
         7 . A nucleic acid comprising a nucleotide sequence encoding an siRNA, wherein said siRNA, when produced in a eukaryotic cell, reduces the level of sulfatase polypeptide produced by the cell.  
     
     
         8 . The nucleic acid according to  claim 7 , wherein said siRNA, when produced in a eukaryotic cell, reduces the level of human sulfatase-1 polypeptide produced by the cell.  
     
     
         9 . The nucleic acid according to  claim 7 , wherein said siRNA, when produced in a eukaryotic cell, reduces the level of human sulfatase-2 polypeptide produced by the cell.  
     
     
         10 . An expression cassette comprising a transcriptional initiation region functional in an expression host, a nucleic acid according to  claim 7 , wherein said siRNA-encoding nucleotide sequence is under the transcriptional regulation of said transcriptional initiation region, and a transcriptional termination region functional in said expression host.  
     
     
         11 . A method of reducing tumor growth in an individual having an autocrine Wnt signaling tumor, the method comprising: 
 administering to the individual an effective amount of an agent that inhibits binding of a sulfatase to a cell surface plasma membrane.    
     
     
         12 . The method of  claim 11 , wherein said agent is selected from a polypeptide comprising a hydrophilic domain of a sulfatase polypeptide, an antibody or functional fragment thereof, and a small molecule.  
     
     
         13 . The method of  claim 11 , wherein said administering is at or near the site of the tumor.  
     
     
         14 . A method of reducing tumor growth in an individual having an autocrine Wnt signaling tumor, the method comprising: 
 administering to the individual an effective amount of an agent that reduces the level of sulfatase activity in a cell.    
     
     
         15 . The method of  claim 14 , wherein said agent is a nucleic acid comprising a nucleotide sequence encoding an siRNA that, when produced in a eukaryotic cell, reduces the level of sulfatase polypeptide produced by the cell.  
     
     
         16 . The method of  claim 14 , wherein said siRNA, when produced in a eukaryotic cell, reduces the level of human sulfatase-1 polypeptide produced by the cell.  
     
     
         17 . The method of  claim 14 , wherein said siRNA, when produced in a eukaryotic cell, reduces the level of human sulfatase-2 polypeptide produced by the cell.  
     
     
         18 . The method of  claim 14 , wherein the agent is an antibody that inhibits endoglucosamine-6-sulfatase activity.  
     
     
         19 . The method of  claim 14 , wherein said administering is at or near the site of the tumor.  
     
     
         20 . An isolated antibody or antigen-binding fragment thereof, wherein said antibody or antigen-binding fragment bind specifically to a sulfatase, wherein the sulfatase exhibits endoglucosamine-6-sulfatase activity.  
     
     
         21 . The antibody of  claim 20 , wherein the antibody is a monoclonal antibody.  
     
     
         22 . The antibody of  claim 20 , wherein the antibody inhibits the endoglucosamine-6-sulfatase activity of the sulfatase.  
     
     
         23 . A composition comprising the antibody or fragment of  claim 20;  and a pharmaceutically acceptable carrier.