Adenoviruses mutated in the va genes for cancer treatment

Abstract

This invention refers to the use of an adenovirus for cancer treatment, being this adenovirus defective in its virus-associated (VA) RNAs. Said adenovirus has a mutation in the VAI or VAII gene sequence or both. This adenovirus may also have mutations in the sequences controlling expression of the VA RNAs.

1 .- 11 . (canceled)  
     
     
         12 . An adenovirus having mutated VAI and VAII RNA genes, wherein said adenovirus is defective in its VAI and VAII virus-associated RNAs and will selectively replicate in cells of said cancer, and wherein said adenovirus further has one or more additional mutations to obtain selective replication in tumors.  
     
     
         13 . The adenovirus according to  claim 12 , wherein one or more of said additional mutations to obtain selective replication in tumors is a mutation in one or both of E1a or E1b.  
     
     
         14 . The adenovirus according to  claim 13 , wherein said mutation in one or both of E1a or E1b is a mutation in a promoter region.  
     
     
         15 . The adenovirus according to  claim 12 , wherein said adenovirus further has mutations in the VA RNA genes to obtain selective replication in tumor cells.  
     
     
         16 . The adenovirus according to  claim 12 , wherein said adenovirus further has mutations in the VA RNA genes to obtain selective replication in tumor cells with an active Ras pathway or unresponsive to interferon.  
     
     
         17 . The adenovirus according to  claim 12 , wherein said adenovirus has at least one modification in its capsid to increase its infectivity or to direct it to a receptor present on a tumor cell.  
     
     
         18 . The adenovirus according to  claim 12 , wherein at least one of said additional mutations to obtain selective replication in tumors is an insertion of a promoter that is selectively active in tumor cells, wherein said insertion is in one or more genes of the group E1a, E1b, and E4.  
     
     
         19 . The adenovirus according to  claim 12 , wherein the adenovirus is a human adenovirus.  
     
     
         20 . The adenovirus according to  claim 19 , wherein said adenovirus is a human adenovirus derived from a serotype between 1 and 50, inclusive, that has both a VAI gene and a VAII gene.  
     
     
         21 . The adenovirus according to  claim 19 , wherein said adenovirus is a human adenovirus derived from serotype 5.  
     
     
         22 . The adenovirus according to  claim 12 , wherein said adenovirus further comprises at least one other gene useful in cancer gene therapy.  
     
     
         23 . The adenovirus according to  claim 22 , wherein said gene useful in cancer gene therapy is selected from the group consisting of prodrug activators, tumor suppressors, and immunostimulants.  
     
     
         24 . An adenovirus comprising: 
 (A) one or a combination of (i) a mutation within a VAI gene; (ii) a mutation in a sequence before a VAI gene that controls the expression of said gene; or (iii) a mutation in a sequence after a VAI gene that controls termination of transcription of said gene;    (B) one or a combination of (i) a mutation within a VAII gene; (ii) a mutation in a sequence before a VAII gene that controls the expression of said gene; or (iii) a mutation in a sequence after a VAII gene that controls termination of transcription of said gene; and    (C) one or more additional mutations to obtain selective replication in tumors. wherein said mutations (A) and (B) result in defective VAI and VAII virus-associated RNAs, and wherein said adenovirus will selectively replicate in cells of said cancer.    
     
     
         25 . The adenovirus according to  claim 24 , wherein one or more of said additional mutations to obtain selective replication in tumors is a mutation in one or both of E1 a or E1b.  
     
     
         26 . The adenovirus according to  claim 25 , wherein said mutation in one or both of E1a or E1b is a mutation in a promoter region.  
     
     
         27 . The adenovirus according to  claim 24 , wherein said adenovirus further has mutations in the VA RNA genes to obtain selective replication in tumor cells.  
     
     
         28 . The adenovirus according to  claim 24 , wherein said adenovirus further has mutations in the VA RNA genes to obtain selective replication in tumor cells with an active Ras pathway or unresponsive to interferon.  
     
     
         29 . The adenovirus according to  claim 24 , wherein said adenovirus has at least one modification in its capsid to increase its infectivity or to direct it to a receptor present on a tumor cell.  
     
     
         30 . The adenovirus according to  claim 24 , wherein at least one of said additional mutations to obtain selective replication in tumors is an insertion of a promoter that is selectively active in tumor cells, wherein said insertion is in one or more genes of the group E1a, E1b, and E4.  
     
     
         31 . The adenovirus according to  claim 24 , wherein the adenovirus is a human adenovirus.  
     
     
         32 . The adenovirus according to  claim 31 , wherein said adenovirus is a human adenovirus derived from a serotype between 1 and 50, inclusive, that has both a VAI gene and a VAII gene.  
     
     
         33 . The adenovirus according to  claim 31 , wherein said adenovirus is a human adenovirus derived from serotype 5.  
     
     
         34 . The adenovirus according to  claim 24 , wherein said adenovirus further comprises at least one other gene useful in cancer gene therapy.  
     
     
         35 . The adenovirus according to  claim 34 , wherein said gene useful in cancer gene therapy is selected from the group consisting of prodrug activators, tumor suppressors, and immunostimulants.