Viral vectors and their use for treating hyperproliferative disorders, in particular restenosis

Abstract

The present invention relates to replication defective recombinant viruses which contain at least one inserted gene encoding all or part of the protein GAX or of a variant of this protein, and to their therapeutic use, in particular for treating post-angioplastic restenosis.

We claim:  
     
       1. A method for inhibiting proliferation of mammalian vascular smooth muscle cells, said method comprising locally administering to said cells a replication defective recombinant adenovirus comprising a gene encoding a mammalian GAX protein, wherein said gene is expressed and proliferation of said cells is inhibited. 
     
     
       2. A method according to  claim 1 , wherein the adenovirus is of human or canine origin. 
     
     
       3. A method according to  claim 2 , wherein the adenovirus is a human Ad 5 or Ad 2. 
     
     
       4. A method according to  claim 1 , wherein the protein is a rat GAX protein. 
     
     
       5. A method according to  claim 1 , wherein the protein is a human GAX protein. 
     
     
       6. A method according to  claim 1 , wherein the inserted gene is a cDNA. 
     
     
       7. A method according to  claim 1 , wherein the inserted gene is a gDNA. 
     
     
       8. A method according to  claim 1 , wherein said adenovirus comprises a deletion of all or part of the E1 region. 
     
     
       9. A method according to  claim 8 , wherein said adenovirus additionally comprises a deletion of all or part of the E4 region. 
     
     
       10. A method according to  claim 1 , wherein the gene encoding the mammalian GAX protein is operably linked to a promoter. 
     
     
       11. A method according to  claim 10 , wherein the promoter is a viral promoter. 
     
     
       12. A method according to  claim 11 , wherein the viral promoter is a cytomegalovirus promoter. 
     
     
       13. A method according to  claim 10 , wherein the promoter is a tissue specific promoter. 
     
     
       14. A method according to  claim 13 , wherein the tissue is smooth muscle. 
     
     
       15. A method according to  claim 10 , wherein the promoter is an A method promoter. 
     
     
       16. A method according to  claim 1 , wherein said administering is to cells of a patient at risk of restenosis. 
     
     
       17. A method of inhibiting restenosis in a patient, said method comprising administering to vascular smooth muscle cells at a predetermined site in said patient a replication defective recombinant adenovirus comprising a gene encoding a mammalian GAX protein wherein said gene is expressed in vascular smooth muscle cells of said patient and inhibits proliferation of said cells. 
     
     
       18. A method according to  claim 17 , wherein said site is a site of mechanical injury to an arterial wall produced by treatment of an atherosclerotic lesion by angioplasty. 
     
     
       19. A method according to  claim 18 , wherein the adenovirus is administered with a balloon catheter. 
     
     
       20. A method according to  claim 19 , wherein the catheter is a hydrogel catheter. 
     
     
       21. A method according to  claim 19 , wherein the catheter is a perfusion balloon catheter. 
     
     
       22. A method according to  claim 19 , wherein the catheter is a channelled balloon catheter. 
     
     
       23. A method according to  claim 17 , wherein the adenovirus is of human or canine origin. 
     
     
       24. A method according to  claim 23 , wherein the adenovirus is a human Ad 5 or Ad 2. 
     
     
       25. A method according to  claim 17 , wherein the protein is a rat GAX protein. 
     
     
       26. A method according to  claim 17 , wherein the protein is a human GAX protein. 
     
     
       27. A method according to  claim 17 , wherein the inserted gene is a cDNA. 
     
     
       28. A method according to  claim 17 , wherein the inserted gene is a gDNA. 
     
     
       29. A method according to  claim 17 , wherein said adenovirus comprises a deletion of all or part of the E1 region. 
     
     
       30. A method according to  claim 29 , wherein said adenovirus additionally comprises a deletion of all or part of the E4 region. 
     
     
       31. A method according to  claim 17 , wherein the gene encoding the mammalian GAX protein is operably linked to a promoter. 
     
     
       32. A method according to  claim 31 , wherein the promoter is a viral promoter. 
     
     
       33. A method according to  claim 32 , wherein the viral promoter is a cytomegalovirus promoter. 
     
     
       34. A method according to  claim 31 , wherein the promoter is a tissue specific promoter. 
     
     
       35. A method according to  claim 34 , wherein the tissue is smooth muscle. 
     
     
       36. A method according to  claim 31 , wherein the promoter is an actin promoter. 
     
     
       37. A method according to  claim 2 , wherein the adenovirus is a CAV 2  adenovirus. 
     
     
       38. A method according to  claim 1 , wherein the replication defective recombinant adenovirus is administered in a dose of between about  10   4    and about  10     14    plague - forming units.   
     
     
       39. A method according to  claim 38 , wherein the replication defective recombinant adenovirus is administered in a dose of between about  10   6    and about  10     10    plaque - forming units.   
     
     
       40. A method according to  claim 10 , wherein the gene further comprises a signal sequence, which directs the GAX protein into a secretory pathway of a cell to which the replication defective recombinant adenovirus has been administered. 
     
     
       41. A method according to  claim 4 , wherein the gene encodes a fusion protein consisting of the HA 1  epitope of an influenza virus haemagglutinin fused to the N- terminus of the rat GAX protein, and expression of the epitope can be used to monitor the expression of the GAX protein.   
     
     
       42. A method according to  claim 3 , wherein the GAX protein is a rat GAX protein. 
     
     
       43. A method according to  claim 3 , wherein the GAX protein is a human GAX protein. 
     
     
       44. A method according to  claim 23 , wherein the adenovirus is a CAV 2  adenovirus. 
     
     
       45. A method according to  claim 17 , wherein the replication defective recombinant adenovirus is administered in a dose of between about  10   4    and about  10     14    plaque - forming units.   
     
     
       46. A method according to  claim 45 , wherein the replication defective recombinant adenovirus is administered in a dose of between about  10   6    and about  10     10    plaque - forming units.   
     
     
       47. A method according to  claim 31 , wherein the gene further comprises a signal sequence, which directs the GAX protein into a secretory pathway of a cell to which the replication defective recombinant adenovirus has been administered. 
     
     
       48. A method according to  claim 25 , wherein the gene encodes a fusion protein consisting of the HA 1  epitope of an influenza virus haemagglutinin fused to the N- terminus of the rat GAX protein, wherein expression of the epitope can be used to monitor the expression of the GAX protein.   
     
     
       49. A method according to  claim 24 , wherein the GAX protein is a rat GAX protein. 
     
     
       50. A method according to  claim 24 , wherein the GAX protein is a human GAX protein.