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 in tumor cells 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 the adenovirus 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 selected from the group consisting of 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 human adenovirus is 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 VAR 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 E1a 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 in tumor cells 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 the adenovirus 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 consisting of 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.