Adenoviral vectors for treating diseases

Abstract

Adenoviral vectors, including mutant adenoviruses, that have restriction sites in the E3 region, that facilitate its partial or total deletion, or select genes contained therein, and optionally compositions and methods for substituting heterologous gene(s) in the partially or totally deleted E3 region(s), which heterologous gene(s) being operably linked to endogenous adenoviral transcriptional control sequences will exhibit an expression pattern, both in terms of timing and degree of expression, similar to the endogenous adenoviral gene(s) that it replaces, and further optionally including mutations in other parts of the adenoviral genome, including certain E1B or E1A regions, and that have applications for diagnosing or treating disease, preferably disease involving unwanted cell growth, including cancer.

1 .- 8 . (canceled)  
     
     
         9 . A composition of matter comprising recombinant adenoviral vectors that have restriction sites in the E3 region that facilitate partial or total deletion of the E3 region, or select genes contained therein, wherein, said partially or totally deleted E3 region is substituted with a gene that encodes a heterologous protein, and said gene is optionally operably linked to a tissue specific promoter.  
     
     
         10 .- 11 . (canceled)  
     
     
         12 . A composition of matter as described in  claim 9 , wherein, said heterologous protein is selected from the group consisting of tumor necrosis factor alpha, interferon gamma, an interleukin, a cell suicide protein, and mip-3.  
     
     
         13 . A composition of matter as described in  claim 9  wherein said heterologous protein is a negative selection gene.  
     
     
         14 . A composition of matter as described in  claim 13  wherein said negative selection gene is selected from the group consisting of cytosine deaminase, and thymidine kinase.  
     
     
         15 - 16 . (canceled)  
     
     
         17 . A method for treating cancer in a mammal in need of said treatment, comprising administering to said mammal a therapeutically effective dose of said composition of  claim 9 , wherein, said heterologous protein has anti-cancer activity.  
     
     
         18 . A method as described in  claim 17  wherein said heterologous protein is selected from the group consisting of tumor necrosis factor alpha, interferon gamma, an interleukin, a cell suicide protein, and mip-3.  
     
     
         19 . A method as described in  claim 18  further comprising administering with said composition a chemotherapeutic or immunosuppressive.  
     
     
         20 . A recombinant adenoviral vector comprising restriction sites in the E3 region of said vector which restriction sites facilitate partial or total deletion of an adenoviral gene or genes contained in said E3 region, and substituted for said partial or total deletion of said adenoviral gene or genes a heterologous gene or genes which exhibit an expression pattern substantially similar to the deleted adenoviral gene or genes.  
     
     
         21 . A recombinant adenoviral vector as described in  claim 20 , wherein said heterologous gene is expressed late during the replication phase of said adenoviral vector.  
     
     
         22 . A recombinant adenoviral vector as described in  claim 21 , wherein said heterologous gene is substituted in the E3b region of said adenoviral vector.  
     
     
         23 . A method for treating cancer in a patient in need of said treatment, comprising administering to said patient an adenoviral vector as described in  claim 21 .  
     
     
         24 . A method for treating cancer in a patient in need of said treatment, comprising administering to said patient an adenoviral vector as described in  claim 22 .  
     
     
         25 . A method for sustained expression of a heterologous gene from the E3 region of an adenoviral vector, comprising contacting cancer cells with said adenoviral vector, wherein said adenoviral vector expresses said heterologous gene late during the adenoviral replication cycle.  
     
     
         26 . A method as described in  claim 25  wherein said heterologous gene is in the E3b region of said adenoviral vector.  
     
     
         27 . A recombinant adenoviral vector as described in  claim 20 , wherein said heterologous genes are substituted for the deleted genes ADP and 6.7K/gp10K of said E3 region, and said heterologous genes are operably linked to endogenous adenoviral transcriptional control sequences.