Methods for treating tweak-related conditions

Abstract

The present invention provides methods and agents for the treatment of TWEAK-related conditions, including cardiac, liver, kidney, lung, adipose, skeletal, muscle, neuronal, bone and cartilage conditions. The invention also provides methods for identifying TWEAK agonists or antagonists for the treatment of TWEAK-related conditions. Additionally, the invention provides transgenic animals that express an exogenous DNA encoding a TWEAK polypeptide, or fragments, analogs, or muteins thereof, and methods for using such animals to identify TWEAK agonists or antagonists. The invention further provides methods for diagnosing a disease based on TWEAK expression. The invention also provides methods for affecting cellular differentiation of progenitor cells using TWEAK polypeptides, agonists, or antagonists.

1 .- 42 . (canceled)  
     
     
         43 . A method of treating neurodegeneration in a subject, the method comprising administering, to the subject, an effective amount of a TWEAK antagonist selected from the group consisting of (a) an anti-TWEAK antibody; (b) an anti-TWEAK receptor antibody; or (c) a TWEAK receptor polypeptide fragment.  
     
     
         44 . The method of  claim 43 , wherein the neurodegeneration is non-inflammatory.  
     
     
         45 . The method of  claim 43 , wherein the TWEAK antagonist is capable of interfering with the interaction between TWEAK and its cellular receptor.  
     
     
         46 . The method of  claim 43 , wherein the TWEAK antagonist comprises Fn14-Fc.  
     
     
         47 . The method of  claim 43 , wherein the TWEAK antagonist comprises an anti-TWEAK antibody.  
     
     
         48 . The method of  claim 43 , wherein the TWEAK antagonist comprises an anti-TWEAK receptor antibody.  
     
     
         49 . The method of  claim 47  or  48 , wherein the antibody is human or humanized.  
     
     
         50 . The method of  claim 47  or  48 , wherein the antibody is monoclonal.  
     
     
         51 . The method of  claim 47  or  48 , wherein the antibody is synthetic.  
     
     
         52 . The method of  claim 47  or  48 , wherein the antibody is full length.  
     
     
         53 . The method of  claim 47  or  48 , wherein the antibody is an antibody fragment comprising an antigen binding portion of the antibody.  
     
     
         54 . The method of  claim 43 , wherein the effective amount of a TWEAK antagonist is administered to the subject via a parenteral route.  
     
     
         55 . The method of  claim 43 , wherein the subject is human.  
     
     
         56 . A method for modulating cellular proliferation or differentiation of a progenitor cell, the method comprising 
 treating a progenitor cell with an agent that comprises (i) a TWEAK polypeptide fragment, (ii) an antibody to TWEAK or TWEAK receptor, or (iii) a TWEAK receptor polypeptide fragment.    
     
     
         57 . The method of  claim 56 , wherein the progenitor cell is treated with the agent in vitro.  
     
     
         58 . The method according to  claim 57 , wherein the agent is a TWEAK antagonist that promotes progenitor cell differentiation.  
     
     
         59 . The method of  claim 58 , wherein the TWEAK antagonist is capable of interfering with the interaction between TWEAK and its cellular receptor.  
     
     
         60 . The method according to  claim 58 , wherein the TWEAK antagonist comprises an anti-TWEAK antibody, an anti-TWEAK receptor antibody, or a protein that includes a TWEAK receptor polypeptide fragment.  
     
     
         61 . The method according to  claim 58 , wherein the TWEAK antagonist is a soluble TWEAK receptor polypeptide fragment.  
     
     
         62 . The method according to  claim 58 , wherein the TWEAK antagonist comprises an Fn14-Fc.  
     
     
         63 . The method according to  claim 57 , wherein the agent is a TWEAK agonist that inhibits progenitor cell differentiation or promotes cellular proliferation.  
     
     
         64 . The method according to  claim 63 , wherein the TWEAK agonist comprises a TWEAK polypeptide fragment.  
     
     
         65 . The method according to  claim 64 , wherein the TWEAK polypeptide fragment is a soluble TWEAK polypeptide fragment.  
     
     
         66 . The method according to  claim 63 , wherein the TWEAK agonist comprises a full length TWEAK.  
     
     
         67 . The method according to  claim 63 , wherein the TWEAK agonist comprises an anti-TWEAK receptor antibody.  
     
     
         68 . The method according to  claim 57 , wherein the progenitor cell is selected from the group consisting of: (a) stem cells; (b) totipotent cells; (c) pluripotent cells; (d) multipotent cells; (e) bipotent cells; (f) tissue-specific cells; (g) embryonic cells; and (h) adult cells.  
     
     
         69 . The method according to  claim 57 , wherein the progenitor cell is an undifferentiated adipose, myogenic, or cartilage, bone, or connective tissue cell.  
     
     
         70 . The method according to  claim 57 , wherein the method further comprises progenitor cell or tissue transplantation therapy.  
     
     
         71 . The method according to  claim 57 , wherein the progenitor cell is a ductular progenitor cell, a skeletal muscle progenitor cell, a preadipocyte, or a mesenchymal stem cell.  
     
     
         72 . The method according to  claim 57 , wherein the progenitor cell is a neural stem cell.  
     
     
         73 . The method according to  claim 57 , wherein the progenitor cell is a precursor of a liver cell type, a kidney tubule, a cardiomyocyte, a lung cell type, a skin cell type, a skeletal muscle cell type, an adipocyte, a gastrointestinal cell type, or a pancreatic cell type.  
     
     
         74 . The method according to  claim 57 , wherein the progenitor cell is a precursor cell of a liver cell type.  
     
     
         75 . The method according to  claim 74 , wherein the precursor cell of a liver cell type is an oval cell.  
     
     
         76 . The method of  claim 56 , wherein the progenitor cell is treated with the agent in vivo in a subject.  
     
     
         77 . The method of  claim 76 , wherein the subject is treated for tissue replacement or regeneration with a TWEAK agonist.  
     
     
         78 . The method according to  claim 77 , wherein the TWEAK agonist comprises a TWEAK polypeptide fragment.  
     
     
         79 . The method of  claim 78 , wherein the TWEAK polypeptide fragment is a soluble TWEAK polypeptide fragment.  
     
     
         80 . The method of  claim 77 , wherein the TWEAK agonist comprises a full length TWEAK.  
     
     
         81 . The method according to  claim 77 , wherein the TWEAK agonist comprises an anti-TWEAK receptor antibody.  
     
     
         82 . The method of  claim 77 , wherein the TWEAK agonist causes an expansion in the population of liver, cardiomyocyte, lung, skin, pancreatic, or neural tissue cell types.  
     
     
         83 . The method of  claim 76 , wherein the method further comprises progenitor cell or tissue transplantation therapy.  
     
     
         84 . The method of  claim 76 , wherein the subject is treated for tissue replacement or regeneration with a TWEAK antagonist.  
     
     
         85 . The method of  claim 84 , wherein the TWEAK antagonist is capable of interfering with the interaction between TWEAK and its cellular receptor.  
     
     
         86 . The method of  claim 84 , wherein the TWEAK antagonist is a soluble TWEAK receptor polypeptide fragment.  
     
     
         87 . The method of  claim 84 , wherein the TWEAK antagonist comprises an Fn14-Fc.  
     
     
         88 . The method of  claim 84 , wherein the TWEAK antagonist causes the differentiation of transplanted progenitor cells in the subject.  
     
     
         89 . The method of  claim 76 , wherein the subject is human.