Uses of gdnf and gdnf receptor

Abstract

GDNFRα, GDNFRα extracellular domain (ECD), GDNFRα variants, chimeric GDNFRα (e.g., GDNFRα immunoadhesin), and antibodies which bind thereto (including agonist and neutralizing antibodies) are disclosed. Various uses for these molecules are described, including methods to modulate cell activity and survival by response to GDNFRα-ligands, for example GDNF, by providing GDNFRα to the cell. Also provided are methods for using GDNFRα, GDNF, or agonists thereof, separately or in complex, to treat kidney diseases.

1 - 12 . (canceled) 
     
     
         13 . A polypeptide comprising a sequence selected from the group consisting of:
 (a) a Glial-cell Derived Neurotrophic Factor Receptor a (GDNFRα) extracellular domain (ECD) amino acid sequence;   (b) an allelic variant or mammalian homolog of (a);   (c) a sequence encoded by nucleic acid which hybridizes under stringent conditions to a nucleic acid encoding (a) or (b); and   (d) a sequence derived from (a) or (b) by substitution, deletion, or addition of one or several amino acids in the amino acid sequence of (a) or (b).   
     
     
         14 . The polypeptide of  claim 13 , comprising the amino acid sequence of GDNFRα ECD from SEQ ID NO 2. 
     
     
         15 . The polypeptide of  claim 14 , comprising the amino acid sequence of mature GDNFRα from SEQ ID NO 2. 
     
     
         16 . The polypeptide of  claim 15 , which specifically binds Glial-cell Derived Neurotrophic Factor (GDNF). 
     
     
         17 . The polypeptide of  claim 16 , which is conjugated with, or fused to, a molecule which increases the serum half-life thereof. 
     
     
         18 . The polypeptide of  claim 13  that is soluble GDNFRα. 
     
     
         19 . A composition comprising the polypeptide of  claim 13  and a physiologically acceptable carrier. 
     
     
         20 . The polypeptide of  claim 13  that is chimeric GDNFRα. 
     
     
         21 . The chimeric GDNFRα of  claim 20 , comprising a GDNFRα amino acid sequence fused to an immunoglobulin sequence. 
     
     
         22 . The chimeric GDNFRα of  claim 20 , comprising a GDNFRα amino acid sequence fused to an epitope tag sequence. 
     
     
         23 . A method for identifying a molecule which binds to the GDNFRα, comprising exposing the GDNFRα to the molecule suspected of binding thereto and determining binding of the molecule to the GDNFRα. 
     
     
         24 . The method of  claim 23 , wherein the GDNFRα is soluble GDNFRα. 
     
     
         25 . A method for identifying a molecule which activates GDNFRα, comprising exposing the GDNFRα to a molecule suspected of being capable of activating GDNFRα and measuring activation of GDNFRα. 
     
     
         26 . A method for purifying a molecule which binds to GDNFRα, comprising adsorbing the molecule to GDNFRα immobilized on a solid phase and recovering the molecule from the immobilized GDNFRα. 
     
     
         27 . The method of  claim 26  wherein the GDNFRα is chimeric GDNFRα, comprising a fusion of a GDNFRα extracellular domain sequence to an immunoglobulin constant domain sequence. 
     
     
         28 . An antibody that specifically binds to GDNFRα of  claim 13 . 
     
     
         29 . The antibody of  claim 28 , which is a monoclonal antibody. 
     
     
         30 . A composition comprising the antibody of  claim 29  and a physiologically acceptable carrier. 
     
     
         31 . The composition of  claim 30  further comprising a cytokine or a neurotrophic factor. 
     
     
         32 . A method for activating GDNFRα, comprising exposing GDNFRα to an amount of an agonist antibody of  claim 28  which is effective for activating GDNFRα. 
     
     
         33 . A method for modulating a physiological response of a cell to GDNF, comprising contacting the cell with an amount of a GDNFRα effective for modulating the response of the cell to GDNF. 
     
     
         34 . A method for determining the presence of GDNFRα, comprising exposing a test sample suspected of containing the GDNFRα to the antibody of  claim 28  and determining binding of said antibody to the test sample. 
     
     
         35 . A nucleic acid molecule comprising a nucleic acid sequence encoding GDNFRα of  claim 13 . 
     
     
         36 . The nucleic acid molecule of  claim 35 , further comprising a promoter operably linked to the nucleic acid molecule. 
     
     
         37 . The nucleic acid molecule of  claim 35 , wherein the nucleic acid sequence encodes GDNFRα ECD. 
     
     
         38 . The nucleic acid molecule of  claim 35 , wherein the nucleic acid sequence encodes chimeric GDNFRα. 
     
     
         39 . An expression vector comprising the nucleic acid molecule of  claim 35  operably linked to control sequences recognized by a host cell transformed with the vector. 
     
     
         40 . A host cell comprising the vector of  claim 39 . 
     
     
         41 . A nucleic acid comprising a nucleic acid sequence of at least 18 contiguous nucleotides from GDNFRα. 
     
     
         42 . A process of using a nucleic acid molecule encoding GDNFRα to effect production of GDNFRα, comprising culturing the host cell of  claim 40  under conditions allowing expression of GDNFRα. 
     
     
         43 . The process of  claim 42  further comprising recovering the GDNFRα from the host cell culture. 
     
     
         44 . A non-human, transgenic animal which contains cells that express nucleic acid encoding GDNFRα polypeptide. 
     
     
         45 . A non-human, knockout animal which contains cells having an altered GDNFRα gene. 
     
     
         46 . A method of treating kidney disease, comprising administering to a patient in need of treatment a therapeutically effective amount of GDNF or GDNF agonist. 
     
     
         47 . The method of  claim 46 , wherein the GDNF is human GDNF. 
     
     
         48 . The method of  claim 46 , further comprising administration of GDNFRα. 
     
     
         49 . The method of  claim 46 , wherein the kidney disease is associated with glomerulonephritis. 
     
     
         50 . A method of treating an enteric nervous system-related disorder, comprising administering to a patient in need of such treatment a therapeutically effective amount of GDNF or GDNF agonist. 
     
     
         51 . The method of  claim 50 , wherein the GDNF is human GDNF. 
     
     
         52 . The method of  claim 50 , further comprising administration of GDNFRα.