Enzyme-prodrug therapy for prosthetic joint repair

Abstract

The invention relates to the use of gene therapy in the treatment of aseptic loosening of orthopaedic prostheses and discloses methods of refixing such prostheses without open revision surgery. In particular, it provides adenoviral vectors and prodrugs for simultaneous, separate or sequential use in the destruction of interface tissue allowing subsequent recementing of loose prostheses in a minimally invasive manner.

1 . A method for reducing interface tissue causing aseptic loosening of orthopaedic implants comprising:
 a) administering to interface tissue cells by intra-articular or periprosthetic injection an effective amount of at least one vector comprising a polynucleotide encoding an enzyme capable of converting a prodrug into an active cytotoxic compound, expression of the enzyme being controlled by an operably-linked promoter; and   b) administering an effective amount of a prodrug capable of being converted into an active cytotoxic compound by said enzyme, to said interface tissue; and   c) allowing the expression of said enzyme in said interface tissue cells, wherein interface tissue is reduced.   
     
     
         2 . The method according to  claim 1 , wherein the promoter provides non-cell type specific expression. 
     
     
         3 . The method according to  claim 2 , wherein the promoter is a cytomegalovirus promoter. 
     
     
         4 . The method according to  claim 1 , wherein the promoter provides substantially cell-type specific expression. 
     
     
         5 . The method according to  claim 4 , wherein expression is substantially restricted to cells of the monocyte/macrophage lineage. 
     
     
         6 . The method according to  claim 5  wherein expression is substantially restricted to osteoclasts and osteoclast precursor cells. 
     
     
         7 . The method according to  claim 1 , wherein the promoter is naturally functionally linked to a gene selected from the group consisting of; TRAP, RANK and cathepsin K. 
     
     
         8 . The method according to  claim 1  wherein the enzyme is a cytochrome P450. 
     
     
         9 . The method according to  claim 8 , wherein the prodrug is acetaminophen. 
     
     
         10 . A method of treating aseptic loosening of orthopaedic implants comprising:
 a) administering to interface tissue cells by intra-articular or periprosthetic injection to a human or other animal an effective amount of a vector comprising a polynucleotide encoding an enzyme capable of converting a prodrug into an active cytotoxic compound, expression of the enzyme being controlled by an operably-linked promoter;   b) allowing the expression of said enzyme in said interface tissue cell's;   c) administering an effective amount of a prodrug capable of being converted into a cytotoxic compound by said enzyme to said interface tissue; and   d) refixing the orthopaedic implant.   
     
     
         11 . The method of  claim 10  wherein the prodrug is administered by intra-articular or periprosthetic injection. 
     
     
         12 . The method of  claim 10  wherein expression of said enzyme is controlled by a promoter that provides non-cell type specific expression. 
     
     
         13 . The method of  claim 10 , wherein expression of said enzyme is controlled by a promoter that provides substantially cell-type specific expression. 
     
     
         14 . The method of  claim 13 , wherein expression is substantially restricted to cells of the monocyte/macrophage lineage. 
     
     
         15 . The method of  claim 14 , wherein expression is substantially restricted to osteoclasts or osteoclast precursors. 
     
     
         16 . The method of  claim 10 , wherein the promoter is naturally functionally linked to a gene selected from the group consisting of; TRAP, RANK and cathepsin K. 
     
     
         17 . The method of  claim 10 , wherein the enzyme is a cytochrome P450. 
     
     
         18 . The method of  claim 17 , wherein the prodrug is acetaminophen.