Gene therapy for restenosis using an adenoviral vector

Abstract

A method for treating restenosis by gene therapy is disclosed, said method comprising delivering a recombinant suicide-gene-containing adenovirus.

1 . Use of a defective recombinant adenovirus containing a suicide gene for the preparation of a pharmaceutical composition intended for the treatment of restenosis.  
     
     
         2 . Use of a defective recombinant adenovirus containing a suicide gene for the preparation of a pharmaceutical composition intended for the treatment of restenosis by selective transfer of the said gene into the smooth muscle cells of the atheromatous plaque.  
     
     
         3 . Use according to  claim 1  or  2 , characterized in that the suicide gene is chosen from the thymidine kinase gene and the cytosine deaminase gene.  
     
     
         4 . Use according to  claim 1  or  2 , characterized in that the suicide gene is the human herpesvirus thymidine kinase (HSV-1 TK) gene.  
     
     
         5 . Use according to one of the preceding claims, characterized in that the suicide gene is placed under the control of a promoter permitting its expression in infected cells.  
     
     
         6 . Use according to  claim 5 , characterized in that the promoter is chosen from viral promoters, preferably the RSV LTR and CMV promoter.  
     
     
         7 . Use according to one of the preceding claims, characterized in that the adenovirus comprises the ITRs, a sequence permitting encapsidation and the suicide gene.  
     
     
         8 . Use according to  claim 7 , characterized in that the adenovirus comprises the ITRs, a sequence permitting encapsidation and the suicide gene, and in which the E1 gene and at least one of the genes E2, E4, L1-L5 is non-functional.  
     
     
         9 . Use according to  claim 8 , characterized in that the adenovirus comprises the ITRs, a sequence permitting encapsidation and the suicide gene, and in which the E1 gene and the E4 gene is rendered nonfunctional.  
     
     
         10 . Use according to  claim 9 , characterized in that the adenovirus comprises the ITRs, a sequence permitting encapsidation and the suicide gene, and in which all or part of the E1 and E4 regions are deleted.  
     
     
         11 . Use according to one of the preceding claims, characterized in that the adenovirus is an adenovirus of human origin, preferably chosen from the serotypes Ad2 and Ad5.  
     
     
         12 . Use according to one of  claims 1  to  10 , characterized in that the adenovirus is an adenovirus of animal origin, preferably chosen from canine adenoviruses.  
     
     
         13 . Use according to one of  claims 1  to  12 , characterized in that the adenovirus is impregnated in a hydrogel.  
     
     
         14 . Use according to  claim 13 , characterized in that the hydrogel is deposited on a balloon catheter.  
     
     
         15 . Use according to  claim 11 , characterized in that the adenovirus is administered via a balloon catheter of the perfusion catheter type.  
     
     
         16 . Use according to  claim 15 , characterized in that the adenovirus is administered via a catheter of the channelled balloon catheter type.  
     
     
         17 . Use according to  claim 15 , characterized in that the adenovirus perfused via a catheter of the perfusion balloon catheter type is impregnated in a hydrogel.  
     
     
         18 . Use according to one of  claims 1  to  12 , characterized in that the adenovirus is impregnated in poloxamer.  
     
     
         19 . Use according to  claim 15 , characterized in that the adenovirus perfused via a catheter of the perfusion balloon catheter type is impregnated in poloxamer.  
     
     
         20 . Pharmaceutical composition comprising a defective recombinant adenovirus impregnated in a hydrogel.  
     
     
         21 . Pharmaceutical composition according to  claim 20 , characterized in that the defective recombinant adenovirus contains a suicide gene.  
     
     
         22 . Device for the percutaneous administration of genes, characterized in that it comprises a balloon catheter coated with a hydrogel, the hydrogel being impregnated with a defective recombinant adenovirus containing the said gene.  
     
     
         23 . Device according to  claim 22 , characterized in that the administration of genes is carried out selectively at the atheromatous plaque.  
     
     
         24 . Device according to  claim 23 , characterized in that the administration of genes is carried out selectively at the smooth muscle cells.  
     
     
         25 . Device according to  claim 24 , characterized in that, when genes are administered, this administration takes place with a selectivity of greater than 95%.  
     
     
         26 . Device according to  claims 23  to  25 , characterized in that the administration of genes is followed by a treatment with ganciclovir.  
     
     
         27 . Device according to  claim 26 , characterized in that the percentage of infected cells is greater than or equal to 0.2%.  
     
     
         28 . Method of therapeutic treatment of restenosis, characterized in that it comprises the percutaneous administration of genes by means of a balloon catheter coated with a hydrogel, the hydrogel being impregnated with a defective recombinant adenovirus containing the said gene.  
     
     
         29 . Method of therapeutic treatment of restenosis according to  claim 28 , characterized in that the administration of genes takes place selectively at the atheromatous plaque.  
     
     
         30 . Method of therapeutic treatment of restenosis according to  claim 29 , characterized in that the administration of genes takes place selectively at the smooth muscle cells.  
     
     
         31 . Method of therapeutic treatment of restenosis according to  claim 30 , characterized in that the administration of genes takes place with a selectivity of greater than 95%.  
     
     
         32 . Method of therapeutic treatment of restenosis according to  claim 31 , characterized in that the administration of TK suicide genes is followed by a treatment with ganciclovir.  
     
     
         33 . Method of therapeutic treatment of restenosis according to  claim 32 , characterized in that it induces a “bystander” effect.  
     
     
         34 . Method of therapeutic treatment of restenosis according to  claim 33 , characterized in that this induced bystander effect permits a therapeutic efficacy even with a small percentage of infected cells.  
     
     
         35 . Method of therapeutic treatment of restenosis according to  claim 34 , characterized in that the percentage of infected cells is greater than or equal to 0.02%.