Methods and compositions for lowering the level of tumor necrosis factor (TNF) in TNF-associated disorders

Abstract

The present invention provides recombinant adeno-associated virus (rAAV) vectors encoding a tumor necrosis factor (TNF) antagonist and methods using these vectors to reduce levels of TNF in a mammal. The invention also provides methods of using these rAAV vectors in palliating TNF-associated disorders.

1 - 39 . (canceled)  
     
     
         40 . A method for treating arthritis in a mammal, comprising administering by intra-articular injection to an arthritic joint of the mammal a recombinant adeno-associated virus (rAAV) vector comprising a polynucleotide encoding a fusion polypeptide comprising an extracellular domain of tumor necrosis factor receptor (TNFR) and a constant domain of an IgG1 molecule, in conjunction with administration of a polypeptide TNF antagonist.  
     
     
         41 . The method of  claim 40 , wherein the rAAV vector is administered by injection to connective tissue selected from the group consisting of a synovium, a cartilage, a ligament, and a tendon of the mammal.  
     
     
         42 . The method of  claim 40 , wherein the rAAV vector is administered to synovial cells lining a joint space of the mammal.  
     
     
         43 . The method of  claim 40 , wherein the TNFR extracellular domain is from p75 TNFR.  
     
     
         44 . The method of  claim 40 , wherein the polynucleotide encoding the TNFR polypeptide is operably linked to a heterologous promoter.  
     
     
         45 . The method of  claim 40 , wherein the polynucleotide encoding the TNFR polypeptide is operably linked to a constitutive promoter.  
     
     
         46 . The method of  claim 40 , wherein the polynucleotide encoding the TNFR polypeptide is operably linked to an inducible promoter.  
     
     
         47 . The method of  claim 46 , wherein the inducible promoter is from the TNFα gene.  
     
     
         48 . The method of  claim 40 , wherein the polynucleotide further encodes a polypeptide comprising an interleukin-1 (IL-1) antagonist.  
     
     
         49 . The method of  claim 48 , wherein the IL-1 antagonist is an IL-1 receptor polypeptide, wherein said IL-1 receptor polypeptide binds IL-1.  
     
     
         50 . The method of  claim 49 , wherein the IL-1 receptor polypeptide is a IL-1 receptor type II polypeptide.  
     
     
         51 . The method of  claim 40 , wherein the TNF antagonist is a polypeptide comprises extracellular domain of TNFR.  
     
     
         52 . The method of  claim 40 , wherein the TNF antagonist is an anti-TNF antibody.  
     
     
         53 . The method of  claim 40 , wherein the mammal is a human.  
     
     
         54 . A method for treating arthritis in a mammal, comprising administering by intra-articular injection to an arthritic joint of the mammal a recombinant adeno-associated virus (rAAV) vector comprising a polynucleotide encoding a fusion polypeptide comprising an extracellular domain of tumor necrosis factor receptor (TNFR) and a constant domain of an IgG1 molecule, whereby arthritic condition in an uninjected contralateral joint is treated.  
     
     
         55 . A method for treating arthritis in a mammal, comprising administering by intra-articular injection to an arthritic joint of the mammal a recombinant adeno-associated virus (rAAV) vector comprising a polynucleotide encoding a fusion polypeptide comprising an extracellular domain of tumor necrosis factor receptor (TNFR) and a constant domain of an IgG1 molecule, in conjunction with administration of a polypeptide TNF antagonist whereby arthritic condition in an uninjected contralateral joint is treated.